Abstract
Purpose
To investigate whether serum hormone (testosterone, prolactin, gonadotropins, and thyroid hormones) and vitamin (vitamin B12, folic acid, and vitamin D) levels are associated with premature ejaculation (PE).
Materials and Methods
This prospective case-control study included 126 patients with PE (lifelong PE [LPE] in 94 and acquired PE [APE] in 32) who presented to the urology outpatient clinic between April 2016 and January 2023 and 92 healthy men as a control group. The diagnosis of PE was based on the criteria defined by the International Society for Sexual Medicine. Serum total testosterone (TT), free and bioavailable testosterone, follicle-stimulating hormone, luteinizing hormone, prolactin, thyroid-stimulating hormone, free triiodothyronine, thyroxine (fT4), vitamin B12, folic acid, and vitamin D levels were measured.
Results
Serum TT, fT4, and vitamin D levels were significantly higher in patients with PE than in the control group (p=0.022, p=0.002, and p=0.044, respectively). However, the serum vitamin B12 level was significantly lower in the PE group (p=0.021). In the multivariate logistic regression analysis, only vitamin B12 was found to be an independent risk factor for PE, with an estimated odds ratio of 0.997 (95% confidence interval 0.994–0.999, p=0.036).
Conclusions
This study demonstrated that lower vitamin B12 levels are associated with the presence of PE. Therefore, we believe that it would be beneficial to consider vitamin B12 levels in the evaluation of patients with PE.
Keywords: Hormone, Premature ejaculation, Vitamin B12, Vitamin D
INTRODUCTION
The prevalence of premature ejaculation (PE), which is the most common sexual dysfunction in men, has been reported to range from 20% to 33% in various populations [1,2]. Although the exact etiopathogenesis of PE has not yet been fully elucidated, it has been hypothesized that the endocrine system plays a role in addition to psychogenic, somatic, neurobiological, and/or genetic factors [3,4]. The potential hormones involved in the regulation of ejaculation include gonadal, pituitary (prolactin and gonadotropins), and thyroid hormones, and various mechanisms have been proposed to explain their role in the process [4].
Ejaculation is controlled by a highly complex set of reflexes involving the central and peripheral nervous systems and is under the neurochemical control of various neurotransmitters, such as serotonin (5-HT), dopamine, and nitric oxide (NO) [5]. While the overall effect of 5-HT is to delay ejaculation, dopamine stimulates ejaculation. Testosterone and thyroid hormones may affect the ejaculation reflex through their receptors, which are expressed in the central and peripheral nervous systems as well as in the male genital tract [6,7]. In addition, a significant reduction in 5-HT levels in the brain has been demonstrated after long-term testosterone treatment in a rat model [8]. Moreover, it has been hypothesized that low prolactin may be a manifestation of decreased central serotonergic and/or increased dopaminergic tone [9].
Folic acid, vitamin B12, and vitamin D may affect ejaculation indirectly by affecting neurotransmitter synthesis. Folic acid and vitamin B12 are known to be important cofactors in the formation of S-adenosylmethionine and tetrahydrobiopterin, which are intermediates in the synthesis of 5-HT and NO [10]. In addition, vitamin D has a regulatory effect on NO and NO synthase [11].
This study aimed to investigate whether serum hormone (testosterone, prolactin, gonadotropins, and thyroid hormones) and vitamin (folic acid, vitamin B12, and vitamin D) levels were associated with PE.
MATERIALS AND METHODS
1. Study design and population
This prospective case-control study included 126 patients with PE who presented to the urology outpatient clinic at Istanbul Training and Research Hospital between April 2016 and January 2023 and 92 healthy men who served as a control group. The diagnosis of PE was based on the criteria defined by the International Society for Sexual Medicine [12]. In addition, in all patients, the diagnosis of PE was confirmed by using the Premature Ejaculation Diagnostic Tool (PEDT) questionnaire and self-reported intravaginal ejaculation latency time (IELT) [13]. IELT values of less than 60 and less than 180 seconds for lifelong PE (LPE) and acquired PE (APE), respectively, and a PEDT score greater than 11 were considered indicative of PE [13]. LPE or APE was categorized on the basis of a detailed sexual history. Erectile function was evaluated by using the International Index of Erectile Function-5 (IIEF-5) questionnaire, and a IIEF-5 score of less than 22 was accepted as erectile dysfunction [14]. The control group was selected from among volunteers who presented to the clinic for a checkup or with complaints other than sexual disorders. Both groups consisted of individuals aged 18 to 45 years who had been engaging in regular heterosexual intercourse with a single partner for at least 6 months.
The exclusion criteria of the study were as follows: (i) the presence of erectile dysfunction; (ii) a history of neurologic or psychiatric disease, urogenital surgery, thyroid disease, diabetes, prostatitis, chronic liver or renal failure, malignancy, or chronic disease; (iii) anatomical abnormalities; (iv) any sexual disorder in the partner; and (v) the use of antidepressants (tricyclic or serotonin reuptake inhibitors), antipsychotics, alpha-blockers, 5-alpha reductase inhibitors, androgens, phosphodiesterase inhibitors, anticholinergics, topical local anesthetics, or vitamin supplements. The flow-chart of the study is shown in Fig. 1.
Fig. 1. Study flowchart. PE, premature ejaculation; LPE, lifelong premature ejaculation; APE, acquired premature ejaculation; PEDT, Premature Ejaculation Diagnostic Tool; IELT, intravaginal ejaculation latency time; IIEF-5, International Index of Erectile Function-5. a:Patients who refused to participate in the study or who did not meet the inclusion criteria were excluded.
All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). The present study protocol was reviewed and approved by the Institutional Review Board of the Istanbul Training and Research Hospital (approval number: 2015-683) and informed consent was obtained from all individual participants.
2. Laboratory assessment
Peripheral blood samples were collected from all patients between 8 AM and 11 AM after they had fasted for 10 to 12 hours overnight. The levels of total testosterone (TT), albumin, sex hormone-binding globulin, follicle-stimulating hormone, luteinizing hormone, prolactin, thyroid-stimulating hormone, free triiodothyronine (fT3), thyroxine (fT4), vitamin B12, folic acid, and vitamin D were measured. In addition, considering the fluctuation of serum vitamin D levels throughout different seasons because of the association with exposure to sunlight, the dates of examination for all patients were recorded. Laboratory tests were repeated a few days later in the event of any abnormal findings. All laboratory tests were performed by experienced staff in the same tertiary hospital laboratory.
Free testosterone and bioavailable testosterone levels were calculated from the known values of TT, sex hormone-binding globulin, and albumin by using a calculator available online (http://www.issam.ch/freetesto.htm) [15].
3. Statistical analysis
Statistical analysis was performed using STATA version 11 (StataCorp LP). The sample size calculation was based on changes in serum vitamin B12 levels. The rates of type I error a and b were 0.05 and 0.10, respectively. The two-tailed p-value was <0.05. The ratio of the study group to the control group was 1:1. It was determined that at least 89 patients were required for each group in the final analysis. The normality of the distributions of the variables was checked by using the Kolmogorov–Smirnov test. Among the descriptive statistics, means and standard deviations were used for normally distributed variables, median (interquartile range) values were used for non-normally distributed variables, and percentages (%) were used for categorical variables. Student’s t-test, the Mann–Whitney U test, the chi-square test, and the Kruskal–Wallis test were used for statistical analysis. Post-hoc evaluations were performed with Dunn’s test following the Kruskal–Wallis test. Any resulting significant association was included as continuous data in logistic regression to determine if it could potentially serve as a predictor for PE.
The diagnostic accuracy of vitamin B12 was evaluated by estimating the area under the curve generated by receiver operating characteristic (ROC) analysis. The ROC curve cutoff value was estimated by using the maximum Youden index. Additionally, the sensitivity, specificity, positive predictive value, and negative predictive value were calculated. p<0.05 was taken as the statistically significant limit.
RESULTS
The characteristics and laboratory findings of the 126 patients with PE and 92 control patients are presented in Table 1. The mean ages of the PE and control groups were similar (34.5±6.2 vs. 33.1±6.8, p=0.268). Serum TT, fT4, and vitamin D levels were significantly higher in the PE group than in the control group (p=0.022, p=0.002, and p=0.044, respectively). The serum vitamin B12 level was significantly lower in the PE group (p=0.021). However, in the multivariate logistic regression analysis, only vitamin B12 was found to be an independent risk factor for PE, with an estimated odds ratio (OR) of 0.997 (95% confidence interval [CI] 0.994–0.999, p=0.036) (Table 2). The area under the ROC curve of vitamin B12 for the diagnosis of PE was 0.611 (95% CI 0.532–0.690, p=0.023; Fig. 2). The optimal cutoff value of vitamin B12 determined by the Youden index for predicting PE was 231 ng/L. Considering a vitamin B12 level of less than or equal to 231 ng/L as a positive test result, this parameter had a sensitivity of 64.4% and a specificity of 34.5% in this prediction.
Table 1. Characteristics and laboratory findings of patients with and without PE.
| Variable and reference range | PE group (n=126) | Control group (n=92) | p-value |
|---|---|---|---|
| Age (y) | 34.5±6.2 | 33.1±6.8 | 0.268 |
| BMI (kg/m2) | 25.8±3.0 | 26.4±3.4 | 0.132 |
| PEDT score | 20.3±5.9 | 6.4±2.3 | 0.001 |
| IELT (s) | 60 (10) | 300 (360) | 0.001 |
| IIEF-5 score | 27.3±2.5 | 27.6±2.6 | 0.523 |
| Total testosterone (ng/dL) (300–1,000) | 393 (180) | 357.2 (186) | 0.022 |
| Free testosterone (ng/dL) (4.5–25.0) | 7.3 (1.5) | 6.7 (2.8) | 0.574 |
| Bioavailable testosterone (ng/dL) (108–500) | 179.5 (45) | 170 (64) | 0.705 |
| FSH (mIU/mL) (1.4–15.4) | 4.2 (3.2) | 4.7 (4.7) | 0.512 |
| LH (mIU/mL) (1.2–8.6) | 5 (1.7) | 4.7 (3.3) | 0.829 |
| Prolactin (ng/mL) (3–13) | 10.3 (4.9) | 9.1 (5.5) | 0.103 |
| TSH (mIU/L) (0.2–4.2) | 1.6 (1.2) | 1.6 (0.8) | 0.880 |
| Free T3 (pg/mL) (2.3–4.1) | 3.6±0.5 | 3.6±0.7 | 0.714 |
| Free T4 (ng/dL) (0.9–1.7) | 1.0±0.4 | 0.9±0.2 | 0.002 |
| Vitamin B12 (ng/L) (200–1,000) | 201 (119.9) | 261 (123) | 0.021 |
| Folic acid (ng/mL) (4.6–18.7) | 6.5 (2.7) | 6.3 (3.4) | 0.574 |
| Vitamin D (ng/mL) (12–50) | 16 (11) | 14 (8.2) | 0.044 |
| SHBG (nmol/L) (10–50) | 37.6±17.4 | 31.1±13.3 | 0.046 |
| Albumin (g/dL) (3.5–5.5) | 4.6±0.3 | 4.5±0.3 | 0.049 |
Values are presented as mean±standard deviation or median (interquartile range).
PE, premature ejaculation; BMI, body mass index; PEDT, Premature Ejaculation Diagnostic Tool; IELT, intravaginal ejaculation latency time; IIEF-5, International Index of Erectile Function-5; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone; T3, triiodothyronine; T4, thyroxine; SHBG, sex hormone-binding globulin.
Table 2. Multivariate logistic regression analysis of risk factors for premature ejaculation.
| Variable | OR | 95% CI | p-value |
|---|---|---|---|
| Total testosterone (ng/dL) | 1.001 | 0.999–1.003 | 0.103 |
| Prolactin (ng/mL) | 1.013 | 0.990–1.035 | 0.274 |
| Free T4 (ng/dL) | 1.152 | 0.745–1.779 | 0.523 |
| Vitamin B12 (ng/L) | 0.997 | 0.994–0.999 | 0.036 |
| Vitamin D (ng/mL) | 1.003 | 0.979–1.027 | 0.784 |
| SHBG (nmol/L) | 1.034 | 0.995–1.075 | 0.086 |
| Albumin (g/dL) | 0.594 | 0.135–2.614 | 0.491 |
OR, odds ratio; CI, confidence interval; T4, thyroxine; SHBG, sex hormone-binding globulin.
Fig. 2. Receiver operating characteristic curves of serum vitamin B12 for the prediction of premature ejaculation.
Table 3 presents the clinical and laboratory characteristics of the patients in the LPE (n=94), APE (n=32), and control groups (n=92). Serum TT and fT4 levels were significantly higher in patients with LPE than in the control group (p=0.012 and p=0.001, respectively). The serum vitamin B12 level of the APE group was significantly lower than that of the control group (p=0.023). Other laboratory parameters were comparable in all three groups (p>0.05).
Table 3. Comparison of the data between the LPE, APE, and control groups.
| Variable and reference range | Group | p-value | ||||
|---|---|---|---|---|---|---|
| LPE (n=94) | APE (n=32) | Control (n=92) | LPE vs. APE | LPE vs. control | APE vs. control | |
| Age (y) | 35.4±4.6 | 34.2±6.7 | 33.1±6.8 | 0.534 | 0.759 | 0.214 |
| BMI (kg/m2) | 25.9±2.8 | 25.7±3.5 | 26.4±3.4 | 0.971 | 0.382 | 0.492 |
| PEDT score | 20.8±6.0 | 19.4±5.6 | 6.4±2.3 | 0.482 | <0.001 | <0.001 |
| IELT (s) | 60 (10) | 60 (71.2) | 300 (360) | 0.061 | <0.001 | <0.001 |
| IIEF-5 score | 27.3±2.6 | 27.2±2.4 | 27.6±2.6 | 0.991 | 0.823 | 0.878 |
| Total testosterone (ng/dL) (300–1,000) | 402 (187) | 370 (100) | 357.2 (186) | 0.766 | 0.012 | 0.814 |
| Free testosterone (ng/dL) (4.5–25.0) | 7.3 (1.9) | 7.6 (1.0) | 6.7 (2.8) | 0.551 | 0.974 | 0.572 |
| Bioavailable testosterone (ng/dL) (108–500) | 179 (66) | 184 (31) | 170 (64) | 0.847 | 0.968 | 0.703 |
| FSH (mIU/mL) (1.4–15.4) | 4.2 (2.9) | 4.3 (4.3) | 4.7 (4.7) | 0.776 | 0.482 | 0.887 |
| LH (mIU/mL) (1.2–8.6) | 5 (1.5) | 4.9 (4.6) | 4.7 (3.3) | 0.862 | 0.931 | 0.924 |
| Prolactin (ng/mL) (3–13) | 10 (5.7) | 11.6 (8.3) | 9.1 (5.5) | 0.731 | 0.492 | 0.471 |
| TSH (mIU/L) (0.2–4.2) | 1.7 (1.3) | 1.4 (0.8) | 1.6 (0.8) | 0.924 | 0.351 | 0.733 |
| Free T3 (pg/dL) (2.3–4.1) | 3.6±0.5 | 3.5±0.4 | 3.6±0.7 | 0.727 | 0.873 | 0.974 |
| Free T4 (ng/dL) (0.9–1.7) | 1.1±0.3 | 1.0±0.2 | 0.9±0.2 | 0.333 | 0.001 | 0.094 |
| Vitamin B12 (ng/L) (200–1,000) | 216 (145) | 190 (130) | 261 (123) | 0.520 | 0.360 | 0.023 |
| Folic acid (ng/mL) (4.6–18.7) | 6.5 (2.8) | 7 (2.3) | 6.3 (3.4) | 0.924 | 0.847 | 0.780 |
| Vitamin D (ng/mL) (12–50) | 15.9 (11) | 16.3 (12.1) | 14 (8.2) | 0.539 | 0.172 | 0.121 |
| SHBG (nmol/L) (10–50) | 37.2±14.2 | 38.4±23.5 | 31.1±13.3 | 0.983 | 0.153 | 0.519 |
| Albumin (g/dL) (3.5–5.5) | 4.5±0.3 | 4.6±0.2 | 4.5±0.3 | 0.462 | 0.101 | 0.673 |
Values are presented as mean±standard deviation or median (interquartile range).
LPE, lifelong premature ejaculation; APE, acquired premature ejaculation; BMI, body mass index; PEDT, Premature Ejaculation Diagnostic Tool; IELT, intravaginal ejaculation latency time; IIEF-5, International Index of Erectile Function-5; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone; T3, triiodothyronine; T4, thyroxine; SHBG, sex hormone-binding globulin.
There was no statistically significant difference between the PE and control groups in terms of the season in which serum vitamin D levels were evaluated (Table 4).
Table 4. Distribution of patients according to the season in which serum vitamin D levels were evaluated.
| PE group (n=126) | Control group (n=92) | p-value | ||
|---|---|---|---|---|
| Season | 0.163 | |||
| Spring | 28 | 33 | ||
| Summer | 40 | 22 | ||
| Autumn | 35 | 22 | ||
| Winter | 23 | 15 | ||
Values are presented as number of patients.
PE, premature ejaculation.
DISCUSSION
In this prospective case-control study investigating the relationship between serum hormone and vitamin levels and PE, the results showed that serum TT, fT4, and vitamin D levels were higher in patients with PE than in those without PE. The serum vitamin B12 level was significantly lower in the PE group. However, according to the multivariate logistic regression analysis, only vitamin B12 was an independent risk factor for PE. When patients with PE were divided into APE and LPE subtypes for further analysis, serum TT and fT4 levels were significantly higher in patients with LPE than in the control group. In addition, the serum vitamin B12 level of the APE group was significantly lower than that of the control group. The vitamin D levels were similar between the LPE, APE, and control groups.
Various studies have reported that vitamin B12 and folic acid deficiency are significantly associated with depression because of their negative effects on 5-HT synthesis [16]. This suggests that vitamin B12 and folic acid levels may also be closely related to PE. The results of the present study demonstrated that the vitamin B12 level was an independent risk factor for PE. Moreover, the cutoff value revealed by our ROC curve analysis of vitamin B12 (≤231 ng/L) can be used as an objective measure for the diagnosis of PE. However, folic acid levels in the groups were similar. In the analysis of PE subtypes, vitamin B12 levels were significantly lower in the APE group. Consistent with our findings, in a case-control study by Kadihasanoglu et al. [17], lower vitamin B12 levels were found in patients with PE. The authors also noted that vitamin B12 levels were negatively correlated with the PEDT score and positively correlated with the IELT value. In contrast, Yin et al. [18] found significantly lower serum folic acid levels in patients with PE. They also reported a positive correlation between folic acid concentration and IELT. In light of the above-mentioned findings, serum vitamin B12 levels should also be investigated, especially in patients with APE, considering the possibility that sexual function may improve with vitamin B12 supplementation in these patients.
Although there are conflicting data in the literature regarding the relationship between testosterone levels and PE, the majority of available studies indicate that men with PE have higher serum testosterone levels than those without PE [4,19]. Similarly, the results of the present study demonstrated that patients with PE had significantly higher serum TT levels than did the healthy control group. In addition, the higher testosterone level detected in patients with LPE is consistent with previous studies [19,20]. However, in the multivariate logistic regression analysis, the TT level was not found to be an independent risk factor for PE. Moreover, although free and bioavailable testosterone levels were higher in patients with PE, the differences did not reach significance. Given the available evidence, further studies are needed to better elucidate the effect of testosterone on the ejaculation reflex.
Although variable results have been reported in the literature, numerous studies have associated hyperthyroidism with PE, particularly APE [21]. A recent meta-analysis showed that the OR of PE increased in hyperthyroid patients compared with euthyroid individuals (OR 2.0, 95% CI 0.6–6.9, p=0.03) [22]. In another study, a positive correlation was found between serum thyroid-stimulating hormone levels and IELT (r=0.37, p=0.04) [21]. Moreover, Carani et al. [23] reported that the prevalence of PE decreased from 50% to 15% after normalization of thyroid function with treatment in a group of patients with hyperthyroidism. In the current study, although serum fT4 levels were found to be higher in all patients with PE and in the LPE group compared with the control group, the serum fT4 level was not a risk factor for PE according to the multivariate analysis. However, unlike the previous studies discussed above, we did not include patients with thyroid gland disease in the present study, and our entire cohort was euthyroid. Therefore, these differences in study populations should be taken into account when interpreting our findings.
The results of the present study showed that the serum vitamin D levels of patients with PE were higher than those of the control group. However, when analyzed according to PE subtypes, there was no significant difference between LPE and APE. The limited evidence in the literature suggests that lower vitamin D levels are associated with PE, which is not consistent with our findings. Canat et al. [24] reported lower levels of vitamin D in patients with APE than in a control group. Abd El Aal et al. [25] found similar results in patients with LPE. Moreover, both studies reported the serum vitamin D level to be an important risk factor for PE. However, unlike our investigation, neither study provided information concerning the season in which vitamin D levels were evaluated. This could be considered a limitation given that seasonal changes can affect serum vitamin D levels, with lower serum vitamin D levels being detected in winter than in summer owing to differences in exposure to sunlight [26]. In addition, the number of patients in our study further strengthens our findings.
In the present study, there was no significant difference in the serum prolactin levels of the patients with PE and the control group, which is consistent with a study conducted by Mohseni et al. [27]. However, different results have been reported in other studies investigating the relationship between prolactin and PE. Corona et al. [9] reported a higher prevalence of PE in patients with relatively low prolactin levels. On the other hand, in a large cohort study, El-Sakka et al. [28] revealed a relationship between PE and mild hyperprolactinemia. In brief, the results of studies on the effect of the prolactin level on PE are not yet conclusive.
The single-center study design is among the limitations of this study. In addition, the presence of sexual dysfunction was self-reported, which may have led to some biases. Moreover, in this study where we evaluated PE from a hormonal perspective, the possible effects of confounding factors such as psychogenic (psycho-relational anxiety and relationship problems), neurobiological, and genetic factors, which are among the etiologies of PE, cannot be completely excluded.
CONCLUSIONS
This study demonstrated that lower vitamin B12 levels are associated with the presence of PE. Therefore, we believe that it would be beneficial to consider vitamin B12 levels in the evaluation of patients with PE. Additionally, the inquiry into the potential efficacy of vitamin B12 supplementation in improving ejaculatory control may be an objective of further studies.
Footnotes
CONFLICTS OF INTEREST: The authors have nothing to disclose.
FUNDING: None.
- Research conception and design: Yasar Pazır, Haydar Guler, and Mustafa Kadıhasanoglu.
- Data acquisition: Haydar Guler, Taha Burak Bulut, Emre Ari, Semih Aktas, and Mustafa Kadıhasanoglu.
- Statistical analysis: Yasar Pazır, Haydar Guler, and Mustafa Kadıhasanoglu.
- Data analysis and interpretation: Yasar Pazır, Haydar Guler, Taha Burak Bulut, Emre Ari, Semih Aktas, and Mustafa Kadıhasanoglu.
- Drafting of the manuscript: Yasar Pazır, Haydar Guler, Taha Burak Bulut, Emre Ari, Semih Aktas, and Mustafa Kadıhasanoglu.
- Critical revision of the manuscript: Yasar Pazır, Haydar Guler, and Mustafa Kadıhasanoglu.
- Supervision: Yasar Pazır and Mustafa Kadıhasanoglu.
- Approval of the final manuscript: all authors.
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