The relationship between vitamin D level and erectile dysfunction in patients with type 2 diabetes mellitus

Abstract

Recent studies have suggested that a relationship could exist between 25-hydroxyvitamin D [25(OH)D] deficiency and erectile dysfunction (ED). The present study evaluated the relationship between 25(OH)D levels and ED in male patients with type 2 diabetes mellitus (DM). The study included 98 patients with type 2 DM aged between 18–80 years. The International Index of Erectile Function (IIEF-5) Questionnaire was administered. The patients were divided into three groups according to IIEF-5 scoring: IIEF-5 score between 5–10, severe ED; IIEF-5 score between 11–20, moderate ED; IIEF-5 score between 21–25, no ED. Biochemical parameters, 25(OH)D and hormonal analysis tests were obtained in all patients. All parameters were compared between these three groups. Of 98 patients included in the study, 32 had severe ED, 45 had moderate ED and 21 had no ED. The mean age was 55.12 ± 9.39 years and the mean 25(OH)D level was 13.69 ± 8.15 ng/ml. When the three groups were compared, 25(OH)D levels were significantly lower in patients with the IIEF-5 score between 5–10 (p = 0.020). There was a moderate positive relationship between IIEF-5 score and 25(OH)D level (r = 0.21, p = 0.038). The patients with severe ED have considerably lower 25(OH)D levels.

Keywords:

• Type 2 diabetes mellitus
• vitamin D
• erectile dysfunction
• IIEF-5 score

Introduction

Erectile dysfunction (ED) is defined as the inability to obtain and/or maintain the erection firm enough to achieve a successful sexual intercourse on a regular basis. It is a more common condition in males with type 2 diabetes mellitus [1,2]. The prevalence of diabetic ED varies from 32 to 90% depending on the age and type and duration of diabetes [3]. In addition, erectile dysfunction occurs as the first symptom of diabetes in 12–30% of males, whereas it is considered a predictor for asymptomatic coronary artery disease in subsequent follow-up of diabetic males [4,5]. The pathophysiology of ED in diabetic males is multifactorial, although it is a vascular disorder associated with impairment in endothelial function [6]. Endothelial dysfunction is considered an early marker indicating the development of atherosclerosis [7]. It plays a key role in the pathophysiology of ED and males with penile endothelial dysfunction are more likely to have endothelial damage in the arteries of other organs [8,9]. Recent studies have suggested a relationship between 25-hydroxyvitamin D [25(OH)D] deficiency and increased risk of cardiovascular disease [10]. 25(OH)D is known to increase nitric oxide production in endothelial cells through genomic and nongenomic pathways, inhibits apoptosis and protects endothelial cells against oxidative stress [11–13]. Since endothelial function is considered an important factor in initiating and maintaining penile erection and deficiency in 25(OH)D is known to cause endothelial dysfunction, hence 25(OH)D deficiency is considered to result in erectile dysfunction [14–16]. Recent prospective studies have reported poor glycemic control and prolonged duration of diabetes in two-thirds of patients with diabetes and low vitamin D levels [17]. This finding reflects the effects of 25(OH)D on glycemic control in diabetic patients [18]. On the other hand, low serum 25(OH)D concentrations have been shown to be associated with insulin resistance, obesity, glucose intolerance and fasting hyperglycemia [19–21]. The present study evaluated the relationship between ED and vitamin D levels in type 2 diabetic patients.

Materials and methods

As a result of power analysis the study included 98 consecutive male patients with type 2 diabetes mellitus (DM) aged between 18 and 80 years, who were admitted to diabetes outpatient clinics of our hospital and who had normal kidney (Glomerular filtration rate >90 ml/dk/1.73m²) and liver functions (Alanine aminotransferase <45 U/L and aspartate transferase <34 U/L) and normal life style engaging regular physical activity. The patients with type 1 DM, hyperprolactinemia, prostate cancer, hypogonadism, thyroid disorders , patients who use drugs that cause ED (diuretics, beta-blockers, etc.) or underwent major pelvic surgery, patients with abnormal rectal bleeding (suspected in duration, nodule, fixation, etc.), patients with a past history of total or transurethral prostatectomy, severe cardiovascular and neurologic disease, acute cerebrovascular accident, acute or chronic infection, uncontrolled diabetes, patients with a history of psychiatric disease and those who have received or are currently receiving vitamin D replacement therapy were excluded from the study. The study was approved by local ethics committee. The patients gave their written informed consent according to the Institutional Review Board guidelines and the Declaration of Helsinki. A detailed medical history was obtained from all patients and all underwent physical examination (including weight, height, BMI (body mass index), waist circumference and blood pressure). Blood chemistry (fasting plasma glucose, glycosylated hemoglobin, total cholesterol, high-density lipoprotein cholesterol, triglycerides, creatinine, calcium and phosphate), hormone levels (total testosterone, Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin), 25(OH)D levels and prostate specific antigen (PSA) were obtained. The blood samples were collected between January and March 2016 as vitamin D levels are known to show seasonal variations. Fasting blood samples were withdrawn between 08:00 and 10:00 AM. Blood samples were collected into SST II, LH PST II and EDTA tubes and analyzed simultaneously.

Definition of erectile dysfunction

All patients were administered International Index of Erectile Function (IIEF-5) questionnaire to detect erectile dysfunction [22]. An IIEF-5 score of 21–25 points indicated absence of erectile dysfunction, a score of 11–20 points indicated moderate erectile dysfunction and a score of 5–10 points indicated severe erectile dysfunction. All parameters were compared between these three groups. In addition, the relationship between IIEF-5 score and 25(OH)D level was also evaluated.

Metabolic parameters

Blood glucose levels were studied in whole blood by enzymatic calorimetric methods using commercial devices with an intra- and interassay coefficient variance of 6 and 8%, respectively. Total cholesterol, HDL, triglyceride, calcium and phosphate levels were measured by using enzymatic colorimetric test using a Hitachi 747 autoanalyser (Mito, Ibaragi, Japan). LDL cholesterol levels were calculated using the formula of Friedewald. HbA1c levels were measured by boronate affinity high-performance liquid chromatography (HPLC) as described in the NHANES Laboratory Procedure Manual: Glycohemoglobin.

Hormone analysis

Total testosterone, Prolactin and LH was measured by immunochemoluminescent assays by an automated analyzer (ARCHITECT i2000SR immunoassay analyzer, Abbot Diagnostics, Abbot Park, IL). The coefficients of variation of testosterone measurements were 3.1 and 3.3% within and between runs, respectively. The coefficients of variations for prolactin were 2.3 and 3.3%, for LH 2.8 and 2.9% and for Vitamin D 3.0 and 3.3% within and between runs, respectively.

Statistical analysis

Descriptive statistics (mean, standard deviation, minimum, median and maximum) were used to express continuous variables. Analysis of variance (ANOVA) was used to compare two independent variables with normal distribution. Pearson’s correlation coefficient was used to analyze the relationship between normally distributed two continuous variables and Spearman’s Rho correlation coefficient was calculated to analyze the relationship between two continuous variables that are normally distributed. Chi-square test (or Fisher’s exact test, where appropriate) was used to evaluate the relationship between categorical variables. The level of statistical significance was set at p < 0.05. The statistical analysis was performed using MedCalc Statistical Software version 12.7.7 (MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org; 2013) software package.

Results

Of patients included in the study, 77 (78.5%) met criteria for ED (IIEF-5 < 21), while 21 patients (21.4%) did not have erectile dysfunction. Demographic features, anthropometric measurements. clinical and biochemical parameters of the patients are summarized in Tables 1 and 2. Of the study participants, 34.7% were using only oral antidiabetic medications, 20.4% were only using insulin therapy and 44.9% were using both insulin therapy and oral antidiabetics medications. The mean 25(OH)D level of the all patients was 13.69 ± 8.15 ng/ml. Reference ranges of vitamin D were 7–53 ng/ml for summer and 6.2–45.5 ng/ml for winter according to commercial kit ARCHITECT 25 OH vitamin D. When the patients were divided into three groups according to IIEF-5 scoring (25(OH)D levels were significantly different between the three groups (p = 0.020) (Table 2). In particular, vitamin D levels were significantly different between patients with IIEF-5 score of 5–10 points and patients with IIEF-5 score of 11–20 points (p < 0.016). Age was different between three groups (p = 0.011). The mean age was different particularly between patients with IIEF-5 score of 5–10 points and patients with IIEF-5 score of 21–25 points (p < 0.016). Patients with lower IIEF scores were older than patients with higher IIEF scores. Waist circumference, BMI and duration of diabetes were not different among three groups (Table 1). There were no difference in terms of HbA1c, testosterone, LH, FSH, prolactin and thyroid-stimulating hormone (TSH) levels between three groups (Table 2). There was a moderate positive correlation between IIEF-5 score and 25(OH)D levels (p = 0.038, r = 0.21). When the patients were divided into three groups according to age (<45 years, 45–65 years, and >65 years), there was a moderate positive correlation between IIEF-5 score and 25(OH)D levels in the 45–65 years age group (r = 0.377, p < 0.05). The hormone levels such as testosterone, LH, FSH, prolactin and TSH did not correlate with IIEF-5 score and 25(OH)D levels.

Table 1. Comparison of demographic, antropometric and clinical data according to IIEF-5 scores.

	All Patients (n = 98)	IIEF-5: 21–25 (n = 23)	IIEF-5: 11-20 (n = 45)	IIEF-5: 10-5 (n = 32)	p value
Age (years)	55.12 ± 9.39	50.29 ± 7.53	55.24 ± 9.85	58.13 ± 8.75	.011
BMI (kg/m^2)	27.06 ± 2.25	26.84 ± 2.34	27.15 ± 2.32	27.08 ± 2.13	.874
Waist (cm)	95.82 ± 7.82	95.71 ± 7.22	96.62 ± 8.39	94.75 ± 7.44	.513
Systolic BP (mmHg)	136.99 ± 22.37	139.05 ± 25.43	136.11 ± 23.47	136.87 ± 19.04	.988
Diastolic BP (mmHg)	73.57 ± 11.49	75.95 ± 10.32	72,59 ± 11.55	72.97 ± 12.24	.351
Diabetes duration (years)	7.15 ± 5.71	5.05 ± 3.58	7.33 ± 5.79	8.28 ± 6.47	.218
Erectile dysfunction duration (years)	3.26 ± 3.75	0.05 ± 0.22	3.24 ± 3.11	5.4 ± 4.3	<.01

Table 2. Comparison of all biochemical parameters according to IIEF-5 scores.

	All Patients (n = 98)	IIEF-5: 21–25 (n = 21)	IIEF-5: 11–20 (n = 45)	IIEF-5: 10-5 (n = 32)	p value
HDL (35–55 mg/dl)	39.18 ± 9.82	41.62 ± 10.42	40 ± 8.65	36.44 ± 10.62	.067
LDL (<130 mg/dl)	143.29 ± 70,27	127.14 ± 33.79	137.24 ± 57.39	162.4 ± 97.1	.591
Cholesterol (<200 mg/dl)	204.12 ± 51.11	210.76 ± 78.96	200.2 ± 41.55	204.96 ± 40.62	.872
Potassium (3.5–5.4 mEq/L)	4.47 ± 0.43	4.36 ± 0.49	4.52 ± 0.41	4.49 ± 0.4	.367
Blood urea nitrogen (21–43 mg/dl)	35.36 ± 10.9	31.87 ± 9.47	34.99 ± 9.58	38.17 ± 12.38	.162
Alanine transaminase (0–55 U/L)	27.58 ± 18.2	29.86 ± 14.19	28.7 ± 23.59	24.5 ± 13.13	.230
FSH (1.7–12 mU/mL)	5.79 ± 3.52	5.06 ± 2.47	5.9 ± 4.31	6.12 ± 2.84	.368
LH (5–25 mU/mL)	4.58 ± 1.81	4.10 ± 1.91	4.56 ± 1.9	4.92 ± 1.57	.174
Free T3 (1.71–3.71 pg/dL)	2.68 ± 0.42	2.78 ± 0.39	2.67 ± 0.41	2.65 ± 0.45	.598
Free T4 (0.7–1.48 pg/mL)	1.24 ± 1.33	1.51 ± 2.02	1.05 ± 0.34	1.33 ± 1.63	.388
Calcium (8.2–10.5 mg/dl)	9.55 ± 0.42	9.64 ± 0.46	9.54 ± 0.4	9.49 ± 0.43	.466
Phosphorus (2.8–4 mg/dl)	3.49 ± 0.48	3.52 ± 0.47	3.41 ± 0.48	3.58 ± 0.49	.315
PSA (0–3.8 ng/mL)	1.26 ± 1.33	1.32 ± 1.41	1.33 ± 1.58	1.12 ± 0.86	.845
Vitamin D (25–100 ng/ml)	13.69 ± 8.15	14.19 ± 8.73	15.71 ± 9.34	10.51 ± 4.28	.020
HBA1C (<4–6%)	9.16 ± 2.46	9.55 ± 2.99	8.98 ± 2.39	9.16 ± 2.19	.817
Glucose (70–105 mg/dl)	194.6 ± 97.09	186 ± 83.68	183.9 ± 88.7	215.53 ± 114.3	.551
Sodium (135–145 mEq/L)	139.07 ± 2.7	138.76 ± 2.4	139.4 ± 2.79	138.8 ± 2.69	.538
Creatinine (0.57–1.1 mg/dl)	0.94 ± 0.24	0.9 ± 0.16	0.92 ± 0.25	0.99 ± 0.27	.532
Aspartate transaminase (5–35 U/L)	21.47 ± 8.31	22.57 ± 7.84	21.31 ± 9.15	20.96 ± 7.52	.576
Prolactin (2–18 µg/L)	9.04 ± 6.17	9.46 ± 7.69	8.9 ± 4.51	8.95 ± 7.2	.595
Testosterone (2.5–8.6 nmol/L)	4.49 ± 1.58	4.17 ± 1.07	4.65 ± 1.59	4.49 ± 1.83	.870
TSH (0.35–4.94 mU/ml)	1.62 ± 1.35	1.41 ± 0.86	1.81 ± 1.7	1.5 ± 1.01	.284

Discussion

The present study found a significant relationship between ED and vitamin D deficiency in patients with type 2 DM. In addition, 25(OH)D levels were lower in the severe ED group compared to moderate ED and no ED groups. Epidemiologic studies have reported a risk of erectile dysfunction in approximately 50% of males with type 2 DM [23]. In the Massachusetts male aging study, the rate of erectile dysfunction in diabetic males was 3-fold higher compared to non-diabetic males [4]. The pathophysiology of ED in diabetic males is multifactorial; however, it involves a vascular disorder associated with impairment in endothelial function [6]. Recent studies have highlighted an association between endothelial dysfunction and low serum vitamin D levels [10]. Interestingly, Al-Tamini and Ali reported poor glycemic control particularly in the long-term and prolonged duration of diabetes in two-thirds of diabetic patients with low vitamin D levels [18].

The present study evaluated possible relationship between plasma 25(OH)D levels and erectile dysfunction in male patients with type 2 diabetes mellitus. Eventually we found lower 25(OH)D concentrations in patients with lower IIEF-5 scores. This relationship was even more prominent in the 45–65 years age group. The present study is the first study demonstrating the higher rate of ED in diabetic male patients with vitamin D deficiency. The rate of erectile dysfunction is known to be higher in obese patients with uncontrolled diabetes [3,24]. Recent studies have also established a relationship between obesity and vitamin D deficiency. The reason for this finding is considered to be lower exposure to sunlight and lower bioavailability of vitamin D as well as sequestration of vitamin D by adipose tissue [25–27]. The present study found a significant difference in terms of BMI distribution between vitamin D deficient and vitamin D-insufficient group (p = 0.025). However, the present study was unable to determine a significant relationship between BMI and IIEF-5 score.

There was no significant relationship between testosterone, LH, FSH, prolactin and TSH levels and IIEF-5 score and vitamin D levels. Using the data of LURIC (Ludwigshafen Risk and Cardiovascular Health) study, Wher et al. reported a positive correlation between plasma testosterone levels and 25(OH)D levels and observed that both hormones showed seasonal variations [28]. Wehr et al. and Pilz et al. showed that 25(OH)D could have direct effect on gonadal functions [29–32]. However, the results of the present study are not concordant to their findings.

Type 2 diabetes mellitus and vitamin D deficiency are also known causes of hypogonadism, In this study we excluded the patients with hypogonadism. Although Lunenfeld et al. recomended 12.1 nmol/L as the lower limit of total testosterone levels, we defined total testosterone levels between reference ranges (2.5–8.6 nmol/L) as normal There is no consensus regarding the lower testosterone treshold defining testosterone deficiency. In addition we could not find a correlation between testosterone and 25(OH)D levels [33].

The present study found that the relationship between ED and vitamin D has occurred independently from hormone levels. In this regard, vitamin D levels might be associated to erectile dysfunction through endothelial dysfunction.

In a recent study Canguven et al. showed that if 12 months vitamin D treatment is provided increases in total testosterone levels and IIEF-5 scores could be observed. We can not make any comments on the effects of vitamin D treatment on erectile functions. Since our aim was to determine the association between vitamin D and ED so we did not follow up those patients [34].

In summary, there is a significant relationship between 25(OH)D deficiency and ED in male patients with type 2 diabetes mellitus. This relationship is considered to be mediated by increased nitric oxide production by 25(OH)D in endothelial cells through various pathways, inhibition of apoptosis and prevention of endothelial dysfunction by preventing against oxidative stress. In conclusion, 25(OH)D levels are correlated with ED scores especially in men with type 2 diabetes mellitus aged between 45–65 years.

Disclosure statement

No potential conflict of interest was reported by the authors.