Our results show a similar prevalence of PE in young male patients with Type 1 diabetes and in the age‐matched control population; in diabetic patients with PE, a higher glycemic variability in the hypoglycemic domain is significantly associated with the PEDT score. Bellastella G, Maiorino MI, Olita L, Della Volpe E, Giugliano D, and Esposito K. Premature ejaculation is associated with glycemic control in Type 1 diabetes. J Sex Med 2015;12:93–99.

PE prevalence did not differ significantly between the two groups: pathological values of the PEDT score (>8) and IELT score (<1 minute) were recorded in 24 out of 100 diabetic patients (24%) and in 12 out of 51 controls (23.5%). There were significant associations between hemoglobin A1c and the PEDT score (r = 0.27; P = 0.006) and IELT (r = −0.3; P = 0.01). In the subgroup assessed for glucose variability, the PEDT score was associated with LBGI (r = 0.43; P = 0.01), but not with BGSD (r = 0.1, P = 0.6), MAGE (r = −0.1; P = 0.4), or HBGI (r = 0.1; P = 0.6).

The presence of PE was assessed with the premature ejaculation diagnostic tool (PEDT) and the self‐estimated intravaginal ejaculatory latency time (IELT). Glucose variability was evaluated by continuous glucose monitoring for a 7‐day period with a DexCom G4 CGM system: the mean amplitude of glycemic excursions (MAGEs), low (LBGI) and high (HBGI) blood glucose indices, and the standard deviation of blood glucose (BGSD) were calculated.

One hundred Type 1 diabetic male patients (age < 40 years) and 51 age‐matched nondiabetic control subjects were evaluated for PE. A subgroup of 30 diabetic patients (20 with PE and 10 without) were also evaluated for blood glucose variability.

The aim of this study was to assess the prevalence of PE in Type 1 diabetes and the influence of glycemic control on ejaculatory function.

Introduction Premature ejaculation (PE) can be defined as a male sexual dysfunction characterized by ejaculation which always or nearly always occurs before or within about 1 minute of vaginal penetration, inability to delay ejaculation on all or nearly all vaginal penetrations, and negative personal consequences, such as distress, bother, frustration, or the avoidance of sexual intimacy 1, 2. This definition refers exclusively to lifelong (from the first sexual experiences) PE. A recent evidence‐based unified definition of lifelong and acquired PE by the Second International Society for Sexual Medicine Ad Hoc Committee for the definition of PE specifies that the lifelong form occurs before or within about 1 minute of vaginal penetration and the acquired form is characterized by a reduction in latency time, often to about 3 minutes or less 3. PE is the most common male sexual dysfunction, with prevalence in the general population ranging from 19% to more than 30% 4-7. Nevertheless, the real prevalence of the condition remains unclear because of a lack of a standardized definition until now and of the variability in perception of normal ejaculatory function between countries, patients, and partners. PE was long considered a psychological or learned condition, primarily interpersonally based; however, organic factors, including thyroid diseases, prostatitis, varicocele, drug consumption, a higher cortical representation of the pudendal nerve, impaired central serotoninergic neurotransmission, and glans penis hypersensitivity, can also be involved 8, 9. Moreover, a recent study 10 shows that married men with lifelong PE had significantly lower serum nitric oxide levels than 40 healthy, age‐matched men. Neurobiological and genetic variations may also contribute to the pathogenesis of lifelong PE, which may be maintained and increased by psychological or situational factors 11, 12. Sexual dysfunctions are common in diabetic men 13, 14, but data on PE are scanty. In a sample of 676 Type 2 diabetic patients (mean age 53 years), the overall prevalence of acquired PE was 40.2%, associated with the length of disease and poor diabetic control 15. In the 713 Type 1 diabetic men of the DCCT/EDIC (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group) cohort, most men seek help for ejaculatory dysfunction only after they have had erectile dysfunction (ED) 16. To the best of our knowledge, the prevalence of PE in patients with Type 1 diabetes has never been assessed; this form of diabetes represents a suitable model for assessing the influence of glycemic status per se on ejaculatory function. Therefore, the aim of this study was to investigate the frequency of PE in young male Type 1 diabetic patients and to assess the influence of glycemic control on it.

Patients and Methods One hundred young male patients (<40 years) affected by Type 1 diabetes were consecutively recruited (from September 1, 2013 to April 30, 2014) from those attending the diabetes unit of the university hospital. Patients were on treatment with multiple daily insulin injections or with continuous subcutaneous insulin infusion. Fifty‐one, age‐ and weight‐matched males served as nondiabetic controls and were recruited from young males attending our unit for the ANDROLIFE program, a yearly clinical program in Italy to provide young males free andrological consultation. To be included in the study, all participants must have had sexual activity with a partner within the previous 6 months. After informed consent was obtained, all participants at the initial visit completed a medical history questionnaire, were asked about their sexual activity, with particular regard to the duration of ejaculation, and underwent a physical examination including anthropometric and blood pressure measurements, evaluation of facial and body hair, testicular volume, penis, prostate, gynecomastia, and muscle mass. The presence of PE was assessed according to the European Association of Urology guidelines 8, with the premature ejaculation diagnostic tool (PEDT) 17, a five‐item questionnaire assessing control, frequency, minimal stimulation, distress, and interpersonal difficulty. A score of 8 or less excludes PE. To improve diagnostic specificity, we combined PEDT with the self‐estimated intravaginal ejaculatory latency time (IELT); an IELT of <1 minute confirms the PE diagnosis. We categorized acquired or lifelong PE from the clinical history through specific question. Participants also completed the International Index of Erectile Function‐5: a score >21 excluded ED 18. A subgroup of 30 diabetic patients (20 with PE and 10 without) underwent continuous 7‐day glucose monitoring through the DexCom G4 CGM system (San Diego, CA, USA), comprising a transcutaneous sensor, a transmitter, and a receiver. We analyzed glucose variability by considering the standard deviation of blood glucose (BGSD) readings and by calculating the mean amplitude of glycemic excursions (MAGEs). The MAGE was calculated as the arithmetic mean of the differences between consecutive glycemic peaks and nadirs, but considering only changes in the glycemic values of more than 1 standard deviation (SD). The low (LBGI) and high (HBGI) blood glucose indices were also calculated. The LBGI reflects the frequency and extent of hypoglycemic episodes and is a weighted average of the number of hypoglycemic readings, with progressively increasing weights as blood glucose levels decrease: the LBGI has been associated with risk of hypoglycemia and prediction of severe hypoglycemic episodes 19. The analyses were performed with EasyGV software (www.easygv.co.uk). Nutritional counseling was already provided for all patients, who were trained in carbohydrate counting, correction bolus use, and hypoglycemic and hyperglycemic perception and management. All participants in the study were evaluated for glycemic status, lipid profile, morning testosterone, thyroid hormones, and thyroid‐stimulating hormone concentrations. Assays were performed in the hospital's chemistry laboratory. Results are presented as mean and SD, or median and interquartile range, as appropriate. Differences between frequencies were evaluated by the chi‐squared test or Fisher exact test. Differences between groups were evaluated by the Student's t‐test or rank sum test, as appropriate. Correlations between PEDT score and hormonal or metabolic parameter values were assessed by the Pearson test. A value of P < 0.05 was considered statistically significant.

Results The demographic and clinical characteristics of the participants in the study are summarized in Table 1. As expected, glycemic parameters (fasting glucose and hemoglobin A1c [HbA1c]) were significantly higher in diabetic than control subjects; all other parameters, including testosterone levels, were not different. No patient reported cannabis or other illegal drugs use nor previous antidepressant or dapoxetine treatment. Table 1. Clinical and biochemical characteristics of participants Type 1 diabetes (n = 100) Control (n = 51) P Age (years) 23.4 ± 5.4 23.2 ± 4.7 0.85 Diabetes duration (years) 12 ± 6 / / Weight (kg) 72.8 ± 9.8 75.3 ± 14.4 0.33 BMI (kg/m2) 24.2 ± 3.03 24.5 ± 3.87 0.68 Physical activity, n (%) 21 (21%) 12 (23.5%) 0.94 Fasting glucose (mg/dL) 196.9 ± 93.1 88.2 ± 6.4 <0.001 HbA1c (%) 8.2 ± 1.3 4.6 ± 0.6 / HbA1c (mmol/mol) 66 27 Total cholesterol (mg/dL) 158.2 ± 29.1 169.3 ± 24.7 0.06 HDL cholesterol (mg/dL) 51.9 ± 12.8 53.6 ± 11.4 0.52 LDL cholesterol (mg/dL) 90.2 ± 25.7 97.8 ± 22.7 0.16 Triglyceride (mg/dL) 80.9 ± 37.4 89.7 ± 31.1 0.25 TSH (μUI/mL) 3.2 ± 1.8 1.5 ± 0.6 <0.001 Testosterone (nmol/L) 23.4 ± 5.31 24.2 ± 5.90 0.40 Table 2 shows the prevalence and characteristics of PE and the associated comorbidities in both diabetic and control subjects. Twenty‐four out of 100 (24%) patients with Type 1 diabetes and 12 out of 51 (23.5%) control subjects had PE, with a PEDT score >8 and an IELT score <1 minute: PE prevalence was not significantly different between the two groups (P = 0.89), neither was there a difference in lifelong (P = 1.00) nor acquired (P = 1.00) PE prevalence. Nine out of 24 diabetic patients with PE presented associated comorbidities, while the remaining 15 patients did not have diabetic complications or other comorbidities. Table 2. Prevalence of premature ejaculation and associated comorbidities in both groups Type 1 diabetes (n = 100) Control (n = 51) P PE, n (%) 24 (24%) 12 (23.5%) 0.89 PEDT score 4 (1–8) 6 (3–8) 0.26 IELT (min) 3.8 ± 2.1 4.1 ± 2.5 0.54 Type of PE, n (%) Lifelong 7/24 (25%) 4/12 (33%) 1.00 Acquired 17/24 (70.8%) 8/12 (66.6%) 1.00 Comorbidity, n Genitourinary infections 3/24 0 0.53 Erectile dysfunction 1/24 1/12 1.00 Hypogonadism 1/24 0 1.00 Neuropathy 2/24 0 0.54 Thyroid autoimmunity 2/24 0 0.53 The five items of the PEDT score and the distribution of the answers given by all population (diabetic and control subjects) are shown in Table 3. Table 3. Distribution of answers of all participants to each question of PEDT Score 0 1 2 3 4 Not difficult at all Somewhat difficult Moderately difficult Very difficult Extremely difficult Q1. How difficult is it for you to delay ejaculation? 58 (38.2%) 49 (32.6%) 36 (23.6%) 3 (2.2%) 5 (3.4%) Almost never or never (0%) Less than half the time (25%) About half the time (50%) More than half the time (75%) Almost always or always (100%) Q2. Do you ejaculate before you want to? 60 (39.7%) 44 (29.2%) 32 (21.2%) 10 (6.6%) 5 (3.3%) Almost never or never (0%) Less than half the time (25%) About half the time (50%) More than half the time (75%) Almost always or always (100%) Q3. Do you ejaculate with very little stimulation? 66 (43.7%) 42 (27.8%) 25 (16.5%) 14 (9.3%) 4 (2.6%) Not at all Slightly Moderately Very Extremely Q4. Do you feel frustrated because of ejaculating before you want to? 74 (49%) 39 (25.8%) 24 (15.9%) 14 (9.3%) 0 Not at all Slightly Moderately Very Extremely Q5. How concerned are you that your time to ejaculation leaves your partner sexually unfulfilled? 66 (43.7%) 36 (23.8%) 31 (20.5%) 15 (9.9%) 3 (2.0%) There were significant associations between HbA1c and the PEDT score (r = 0.27; P = 0.006) (Figure 1A) and IELT (r = −0.3; P = 0.01), while the association of the PEDT score with duration of disease was of borderline significance (r = 0.2; P = 0.09). In the subgroup of 30 diabetic patients assessed for glucose variability, the PEDT score was positively associated with LBGI (r = 0.43; P = 0.01) (Figure 1B). There were no correlations between the PEDT score and BGSD (r = 0.1, P = 0.6), MAGE (r = −0.1; P = 0.4), or HBGI (r = 0.1; P = 0.6); similarly, there was no association between the PEDT score and testosterone levels (r = 0.1, P = 0.6). Figure 1 Open in figure viewer PowerPoint Correlation between the premature ejaculation diagnostic tool (PEDT) score and hemoglobin A1c (HbA1c) (A, 100 Type 1 diabetic patients) and low blood glucose index (LBGI) (B, 30 diabetic patients with CGM); patients with premature ejaculation (PE) are to the right of the vertical line. Correlation between intravaginal ejaculatory latency time (IELT) and HbA1c (C, 100 Type 1 diabetic patients); patients with PE are to the left of the vertical line. Correlations were assessed by the Pearson test.

Discussion This study, the first to our knowledge to assess PE in Type 1 diabetes, shows that the prevalence of PE in young patients with this disease is not different from that of age‐matched control subjects. However, we found an association between the PEDT score and that of HbA1c and LBGI, suggesting a role for glycemic control, particularly glycemic variability in the domain of hypoglycemia, in the ejaculatory process. PE is a highly prevalent sexual problem, with an estimated prevalence ranging from 19% to more than 30% 4-7 with little variation across countries: 24.0% in the United States, 20.3% in Germany, and 20–21% in Italy 20, 21. Our results from Type 1 diabetic patients are in line with the findings in the general population. Risk factors for PE in Type 1 diabetes are largely, if not completely, unknown: in order to avoid a selection bias leading to underestimation of the real prevalence of PE in Type 1 diabetes, we specified that the only criterion to be included in the present study was that all participants (diabetic and control subjects) must have had sexual activity with a partner in the previous 6 months. In spite of this loose inclusion criterion and the lack of exclusion criteria, we found a consistent number of young patients showing PE without any comorbidity, particularly ED, suggesting that Type 1 diabetes, in this age range, is not characterized by the association of multiple sexual dysfunctions, such as PE and ED. In Type 2 diabetes, the longer duration of diabetes, worse metabolic control, and presence of cardiovascular comorbidity have all been reported as associated with an increased risk of PE 15. These associations are only based upon the results of one large cross‐sectional study involving 676 Saudi Arabian patients with a diagnosis of Type 2 diabetes: the prevalence of acquired PE was around 40%, and increased with age (32.4% below 50 years vs. 67.6% above 50 years) and duration of disease, as patients with a duration of disease >10 years were 2.7 times more likely to report PE than patients with duration of diabetes <5 years. Unfortunately, the study did not assess the prevalence of PE in the age‐matched nondiabetic population; moreover, the evidence that 95% of Type 2 diabetic patients with PE also reported ED 15 makes it quite hard to dissect the respective roles of underlying factors that predispose these two sexual dysfunctions to aggregate, at least in Type 2 diabetes. The association of the PEDT score and IELT with HbA1c suggests a role for glycemic control in the ejaculatory process. Moreover, the even stronger association of the PEDT score with LBGI in the subset of Type 1 diabetic patients undergoing continuous glucose monitoring seems to indicate a direct link between glycemic excursions and PE. The LBGI is calculated by dividing the daily hypoglycemic risks by the number of days considered; all the values <70 mg/dL are used for analysis and an LBGI > 5 is considered a high hypoglycemic risk. The association of hypoglycemia with PE could be related to activation of the adrenergic system 22 or inhibition of serotoninergic neuronal activity 23, both associated with significant reduction of ejaculation time. This study presents some limitations: the first is that the diagnostic criteria adopted 8 did not provide a difference in IELT between lifelong and acquired forms, but when the study was planned, the recent advances in PE definition and diagnosis were not available. Another limitation is the use of the PEDT questionnaire, which was developed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition definition of PE, which is an outdated definition and its specificity is considered as low as 50% 24. Finally, the correlations we found remain to be confirmed as the correlation coefficients were not very high (r = −0.3 and 0.27 for IELT and PEDT, respectively). Therefore, further studies, which adopt the latest diagnostic criteria, involving many other patients with Type 1 diabetes, are necessary to determine the real prevalence of PE in these patients and to confirm the role of glycemic control.

Conclusions Our results show a similar prevalence of PE in young patients with Type 1 diabetes and in the age‐matched control population, which suggests that this form of diabetes is not a risk factor for PE. However, in diabetic patients with PE, a higher glycemic variability in the hypoglycemic domain was significantly associated with the PEDT score. Whether amelioration of glycemic variability would improve PE in Type 1 diabetic patients remains to be proven in specific interventional studies.

Acknowledgment The authors wish to thank Dr. Trevor G. Cooper, Centre of Reproductive Medicine and Andrology of the University, Munster, Germany, for suggestions in revising the final version of the manuscript.

Conflict of Interest: The authors report no conflicts of interest.

Statement of Authorship Category 1 (a) Conception and Design Giuseppe Bellastella; Maria Ida Maiorino; Katherine Esposito

(b) Acquisition of Data Giuseppe Bellastella; Maria Ida Maiorino; Katherine Esposito; Laura Olita

(c) Analysis and Interpretation of Data Giuseppe Bellastella; Maria Ida Maiorino; Elisabetta Della Volpe; Dario Giugliano; Katherine Esposito Category 2 (a) Drafting the Article Giuseppe Bellastella; Katherine Esposito; Dario Giugliano

(b) Revising It for Intellectual Content Giuseppe Bellastella; Elisabetta Della Volpe; Maria Ida Maiorino; Dario Giugliano; Katherine Esposito Category 3 (a) Final Approval of the Completed Article Giuseppe Bellastella; Maria Ida Maiorino; Elisabetta Della Volpe; Laura Olita; Dario Giugliano; Katherine Esposito