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Vitamin D and Erectile Dysfunction
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Vitamin D and Erectile Dysfunction Alessandra Barassi, MD,* Raffaele Pezzilli, MD,† Giovanni M. Colpi, MD,‡ Massimiliano M. Corsi Romanelli, MD,§¶ and Gian Vico Melzi d’Eril, MD* *Clinical Biochemistry Laboratory, Department of Health Sciences, San Paolo Hospital, University of Milan, Milan, Italy; † Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant’Orsola-Malpighi Hospital, Bologna, Italy; ‡ ISES—Institute for the Infertility and Sexuality, Milan, Italy; §Department of Biomedical Science for Health, University of Milan, Milan, Italy; ¶Operative Unit of Laboratory Medicine, IRCCS Policlinico San Donato, Milan, Italy DOI: 10.1111/jsm.12661
ABSTRACT
Introduction. Endothelial dysfunction has been demonstrated to play an important role in pathogenesis of erectile dysfunction (ED) and vitamin D deficiency is deemed to promote endothelial dysfunctions. Aim. To evaluate the status of serum vitamin D in a group of patients with ED. Methods. Diagnosis and severity of ED was based on the IIEF-5 and its aetiology was classified as arteriogenic (A-ED), borderline (BL-ED), and non-arteriogenic (NA-ED) with penile-echo-color-Doppler in basal condition and after intracaversous injection of prostaglandin E1. Serum vitamin D and intact PTH concentrations were measured. Main Outcome Measures. Vitamin D levels of men with A-ED were compared with those of male with BL-ED and NA-ED. Results. Fifty patients were classified as A-ED, 28 as ED-BL and 65 as NA-ED, for a total of 143 cases. Mean vitamin D level was 21.3 ng/mL; vitamin D deficiency (<20 ng/mL) was present in 45.9% and only 20.2% had optimal vitamin D levels. Patients with severe/complete-ED had vitamin D level significantly lower (P = 0.02) than those with mild-ED. Vitamin level was negatively correlated with PTH and the correlation was more marked in subjects with vitamin D deficiency. Vitamin D deficiency in A-ED was significantly lower (P = 0.01) than in NA-ED patients. Penile-echo-color-Doppler revealed that A-ED (PSV ≤ 25 cm/second) was more frequent in those with vitamin D deficiency as compared with those with vitamin >20 ng/dL (45% vs. 24%; P < 0.05) and in the same population median PSV values were lower (26 vs. 38; P < 0.001) in vitamin D subjects. Conclusion. Our study shows that a significant proportion of ED patients have a vitamin D deficiency and that this condition is more frequent in patients with the arteriogenic etiology. Low levels of vitamin D might increase the ED risk by promoting endothelial dysfunction. Men with ED should be analyzed for vitamin D levels and particularly to A-ED patients with a low level a vitamin D supplementation is suggested. Barassi A, Pezzilli R, Colpi GM, Corsi Romanelli MM, and Melzi d’Eril GV. Vitamin D and erectile dysfunction. J Sex Med **;**:**–**. Key Words. Erectile Dysfunction; Vitamin D; Endothelial Dysfunctions
Introduction
E
rectile dysfunction (ED) is a highly prevalent global health problem with a considerable impact on the quality of life of middle-aged men. The projection for 2025 shows that over 322 million men will have ED [1]. Although nonvas-
© 2014 International Society for Sexual Medicine
cular diseases and conditions are closely related to ED [2], it is primarily a vascular disorder. Its most common cause is the arterial occlusion of atherosclerosis, which also affects the coronary arteries and can lead to a heart attack [3] or, in other parts of the body, vascular events such a stroke [4] and peripheral arterial disease [5]. J Sex Med **;**:**–**
2 Apart from its well-known role in bone and calcium metabolism, vitamin D deficiency has recently received widespread attention. In fact, vitamin D receptors and 1-alpha-hydroxylase, which converts vitamin D into the hormonal 1,25dihydroxyvitamin D form, are present in many tissues including endothelial cells [6]. In particular, vitamin D has recently been shown to modulate endothelial function [7]. In fact, endothelial cells synthesize vitamin D and express vitamin D receptors suggesting the hypothesis of a possible autocrine/intracrine mechanism exerted by vitamin D as a modulator of endothelial functions [8]. Observational data associate lower levels of serum vitamin D with coronary artery calcification, cardiovascular acute and chronic events, stroke and overall mortality [9–12]. In addition, it has been experimentally demonstrated that vitamin D deficiency, as well as excess, increases atherosclerotic calcification; the phenotype of vitamin D deficiency can be induced also before therapeutic measures for cardiovascular diseases associated with vitamin D deficiency and that maintenance of an optimal range of vitamin D signaling may be important for prevention of atherosclerotic calcification [13]. Furthermore, experimental studies showed beneficial vitamin D effects on cardiovascular risk factors, the heart and the blood vessels [14]. For all these reasons we evaluated the vitamin D levels in a group of men in good health with arteriogenic, nonarteriogenic and borderline ED, to assess the differences among the three ED subgroups before the presence of clinical or subclinical atherosclerotic symptoms. Investigation Protocol
In our center, patients complaining of ED are currently investigated by careful history-taking and clinical andrological examination; then, a few days later, by a panel of examinations, including blood tests, complete blood picture, hemoglobin, glycated hemoglobin, glucose, urea, creatinine, hs-PCR, total and HDL cholesterol, triglycerides, transaminases, testosterone, prolactin, 17-βestradiol, urine analysis and 24-hour urinary albumin excretion (microalbuminuria), the International Index of Erectile Function (IIEF) questionnaire and echo-color-Doppler of both cavernous arteries. The IIEF questionnaire is a validated, self-administered tool [15,16], but we only evaluated the answers to the first five (erectile response dominium, IIEF-5) of the 15 questions. Possible scores for the IIEF-5 range from 5 to 25; J Sex Med **;**:**–**
Barassi et al. scores of 22–25 indicate normal erectile function whereas scores of 21 or below indicate ED (mild 16–20, moderate 11–15, severe 5–10, complete ≤ 4) [15]. Penile echo-color-Doppler was performed in basal conditions and after an intracavernous injection of 10 μg prostaglandin E1 (PgE1) [17], and the peak systolic velocity (PSV) and end-diastolic velocity (EDV) were recorded at 5, 10, 15, 20, and 25 minutes after the injection in the proximal portion of the penis. Patients were classified as “arteriogenic” (A-ED) when their PSV was <25 cm/second, “borderline” (BL-ED) with PSV between 25 and 35 cm/second and “nonarteriogenic” (NA-ED) when their PSV was ≥35 cm/second, or ≤35 cm/second but >25 cm/second with concomitant EDV ≤ 0 cm/second [18,19]. If a patient appeared stressed, he was given a second injection of the same dose of PgE1 and all measurements were repeated. The erection quality was estimated 20 minutes after each injection. From 30 to 60 minutes before the penile echocolor-Doppler, participants were placed in a supine position and blood samples were drawn from a cubital vein into EDTA tubes. Samples were centrifuged at 3,000 rpm for 10 minutes. The serum was separated and stored at −80°C until analysis. Patients
The patients included in the study were outpatients complaining of ED consecutively attending our Andrology Unit, Ospedale San Paolo, Milan, in the period May 2011-September 2011 and May 2012September 2012. Out of these ED patients, 50 were classified as arteriogenic (A-ED), 28 as border-line (BL-ED) and 65 as non-arteriogenic (NA-ED) patients, for a total of 143 cases (median age 47 years, range 30–60). The exclusion criteria were the following: age less than 30 years and over 60 years, clinical evidence of congestive heart failure, renal insufficiency, anemia, acute infection or rheumatic diseases within 2 months; clinical evidence from the patient’s clinical history of coronary artery disease, hypertension (>140/90 mm Hg in three consecutive recordings at rest), malignancy, systemic inflammatory disease, hepatopathies or arrhythmias, current smoking, and vitamin supplementation or chronic drug assumption. The patients of the three ED subgroups declared normal physical activity and not to take statins. All patients were referred to a cardiologist for evaluation of ischemic heart disease (IHD). The evaluation consisted of a comprehensive clinical history, physical examination, and resting electro-
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Vitamin D and Erectile Dysfunction cardiogram. The diagnosis of IHD relied on the detection of a 1-mm or more horizontal od downsloping ST segment depression, frequent ventricular premature beats, or typical chest pain during the exercise treadmill test. This investigation conforms to the principles outlined in the Declaration of Helsinki. Signed informed written consent was obtained from all subjects before their participation in the study. No ethical committee approval was required because no additional blood was needed for this study and this was explained thoroughly to all patients who gave their written informed consent also for laboratory tests and also because this procedure has been reported to be acceptable [20,21].
Assays HbA1c was measured using a high performance liquid chromatography (HPLC) method (Bio-Rad, Italy). Plasma glucose, creatinine, urea, total cholesterol, HDL-cholesterol, triglycerides, ALT, AST, prolactin, testosterone and 17-β-estradiol were analyzed with commercially available kits using Modular EVO (Roche, Monza, Italy). Plasma LDL-cholesterol was calculated with the use of Friedewald’s formula. Urinary microalbumin concentration was measured in duplicate in the morning samples on a Behring Nephelometer II analyzer (Siemens, Milan, Italy). In this study serum 25-hydroxyvitamin D was measured to assess vitamin D status as it has a long circulating half-life of approximately 15 days [22]. Serum 25-hydroxyvitamin D levels were measured using by radioimmunoassay (RIA) double antibody assay (DiaSorin, Saluggia, Italy). Within-run coefficient of variation (CV) was 8.6–12.5% and total imprecision CV was 8.2–11.0%; the detection limit of the assay was 1.5 ng/mL. Concentration of vitamin D < 20.0 ng/mL (<50.0 nmol/L) is adopted as “deficient” and between 20.0 to 30.0 ng/mL as “insufficient” while optimal levels were defined as vitamin D > 30.0 ng/mL [23–25]. Serum PTH levels were measured using 1–84 PTH chemiluminescence immunoassay (DiaSorin, Italy). Within-run CV was ≤6% and between-run CV was ≤9%; the detection limit of the assay was 1.5 ng/mL. Statistical Analysis Data are reported as median and range or absolute number and the relative frequency. For statistical analysis the Mann–Whitney U-test was used to compare data between the groups, the Wilcoxon
test for paired data to analyze the correlation between vitamin D and PTH, and the chi-squared test to compare the frequencies between the groups. P values < 0.05 were considered statistically significant. All analyses were carried out by using the SPSS 13.0 statistical package (SPSS Inc., Chicago, IL, USA).
Results
In the ED patients of this study the median IIEF-5 value was 14.0 and the vitamin D level (median, range in ng/mL) was 21.3, 5.7–52.9. Vitamin D deficiency was present in 45.9%, with insufficiency in 33.9%, while only 20.2% had optimal levels. Severe vitamin D deficiency (<10.0 ng/mL) was observed in 5.6% patients. There was a significant difference (P = 0.02) between vitamin D levels in patients with IIEF-5 16–20 (mild ED) and IIEF5 ≤ 10 (severe/complete ED) that were 26.1 (range 11.8–52.9) ng/mL and 19.8 (range 5.7–45.4) ng/mL, respectively. In the patients of this study, vitamin D was negatively associated with PTH (r = −0.57; P < 0.001). The negative association between vitamin D and PTH was more marked in subjects with vitamin D < 20.0 ng/mL (r = −0.58; P < 0.0001) compared with those with levels >30.0 ng/mL (r = −0.079; P = 0.71). Of the 143 men included in the study, 50 patients (35.0%) were classified as having A-ED, 28 patients (19.6%) as having BL-ED and 65 patients (45.4%) as having NA-ED. In A-ED (median age 48; 33–60 years), BL-ED (median age 45; 30–60 years) and NA-ED (median age 46; 31–60 years) the mean of IIEF values were 11 (1–20), 16 (6–20) and 15 (2–21), respectively. Table 1 shows physical and biochemical parameters of the patients in this study. Vitamin D levels in A-ED patients (18.2, 5.7– 38.0) were significantly lower (P = 0.04) than in BL-ED patients (22.5, 10.2–31.4) and (P = 0.01) than in NA-ED patients (25.3, 6.5–52.9), but no difference (P = 0.50) was observed between the levels of vitamin D among BL-ED and NA-ED patients. Furthermore, 30.0% (n = 15) and 61.0% (n = 30) of A-ED, 25.0% (n = 7) and 30.0% (n = 8) of BL-ED, 25.0% (n = 16) and 42.0% (n = 27) of NA-ED, have levels of vitamin D between 20.0 and 29.0 ng/mL and <20.0 ng/mL, respectively. No statistically significant differences (P > 0.05) were found in the three groups regarding the other laboratory parameters evaluated (i.e., creatinine, glucose, ALT, AST, total cholesterol, HDL choJ Sex Med **;**:**–**
4 Table 1
Barassi et al. Clinical and laboratory features of patients with erectile dysfunction
Patients data Age (years) IIEF-5 score PSV Body mass index (kg/m2) Laboratory evaluation Study parameters Vitamin D (pg/mL) Other parametres Creatinine (mg/dL) Glucose (mg/dL) Calcium (mg/dL) ALT (U/L) AST (U/L) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Triglycerides (mg/dL) HbA1c (%) 17-β-estradiol (pg/mL) Prolactin (ng/mL) Testosterone (ng/mL)
A-ED (n = 50)
BL-ED (n = 28)
NA-ED (n = 65)
48 (33–60) 11 (1–20) 20 (8–24)* 23.8 (19.8–25.6)
45 (30–60) 16 (6–20) 31 (24–36) 24.3 (21.5–25.9)
46 (31–60) 15 (2–21) 45 (37–99)** 23.2 (21.5–26.2)
18.2 (5.7–38.0)***
22.5 (10.2–31.4)
25.3 (6.5–52.9)
0.90 (0.55–1.25) 92 (51–109) 9.1 (8.5–9.6) 23 (10–59) 23 (13–63) 200 (113–240) 50 (30–88) 133 (91–153) 103 (48–255) 5.7 (4.8–6.4) 27.5 (11.1–46.6) 9.1 (2.2–28.7) 410 (211–590)
0.97 (0.8–1.13) 95 (75–110) 9.2 (8.4–9.7) 24 (12–65) 27 (14–53) 204 (128–230) 47 (26–87) 129 (90–156) 107 (43–245) 5.5 (4.1–6.3) 25.4 (10–52.3) 9.3 (2.6–29.2) 470 (250–605)
0.90 (0.60–1.80) 90 (58–110) 9.3 (8.5–9.8) 27 (6–76) 27 (10–76) 198 (141–251) 52 (30–94) 125 (95–137) 98 (54–220) 5.3 (4.5–6.2) 22.8 (10–45.8) 8.6 (1.1–21.3) 454 (220–616)
Note: Values are reported as median and range. *P < 0.001 vs. BL-ED and NA-ED **P < 0.001 vs. BL-ED ***P < 0.04 vs. BL-ED and P < 0.01 vs. NA-ED A-ED = arteriogenic erectile dysfunction; BL-ED = borderline arteriogenic erectile dysfunction; NA-ED = non-arteriogenic erectile dysfunction
lesterol, LDL cholesterol, triglycerides, HbA1c, 17-β-estradiol, prolactin and testosterone) (Table 1). On categorizing patients into two groups those with vitamin D deficiency and those without (Table 2) there was no significant difference
Table 2
between the two groups in terms of clinical and metabolic parameters. Patients with severe/ complete ED (IIEF-5 ≤ 10) were more frequent in the group with vitamin D levels <20.0 ng/mL as compared with those in the group with levels >20.0 ng/mL (38.6% vs. 25.3%). Then, there was
Characteristics of patients with and without vitamin D deficiency
Patients data Age (years) IIEF-5 score PSV Body mass index (kg/m2) Laboratory evaluation Creatinine (mg/dL) Glucose (mg/dL) Calcium (mg/dL) ALT (U/L) AST (U/L) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Triglycerides (mg/dL) HbA1c (%) 17-β-estradiol (pg/mL) Prolactin (ng/mL) Testosterone (ng/mL) Note: Values are reported as median and range.
J Sex Med **;**:**–**
Vit D < 20 ng/mL
Vit D > 20 ng/mL
P value
47 (35–60) 12 (1–24) 26 (8–55) 23.8 (21.2–26.2)
46 (30–60) 16 (1–25) 38 (11–99) 22.9 (19.8–25.5)
NS P = 0.008 P < 0.001 NS
0.90 (0.55–1.80) 92 (51–110) 9.1 (8.4–9.5) 27 (10–65) 23 (13–44) 204 (113–240) 51 (37–94) 136 (93–156) 110 (48–255) 5.6 (4.1–6.0) 26 (10–46.6) 10 (3.6–18.6) 430 (220–585)
0.91 (0.60–1.32) 89 (57–103) 9.4 (8.5–9.8) 26 (10–76) 23 (10–63) 199 (135–251) 50 (30–86) 128 (90–141) 99 (43–177) 5.7 (4.8–6.4) 25 (10–52.3) 9 (3.3–29.2) 470 (260–616)
NS NS NS NS NS NS NS NS NS NS NS NS NS
Vitamin D and Erectile Dysfunction a trend toward lower mean vitamin D levels with increasing severity of ED, but this was not statistically significant. However, the median level of IIEF-5 was significantly lower in those with lower vitamin D levels 12 (range 1–24) vs. 16 ([range 1–25]; P = 0.008). In the same two groups there were significantly lower median PSV values with decreasing vitamin D levels. Median PSV values were 26 (8–55) vs. 38 (11–99), respectively for the two groups (P < 0.001). The prevalence of PSV values < 25 (A-ED) was 45.6% vs. 23.9%, respectively, in patients with vitamin D levels <20.0 ng/ mL, and >20.0 ng/mL (P < 0.05). Discussion
Vitamin D (25-hydroxyvitamin D) is considered to be the best indicator of overall vitamin D status of an individual and to reflect the level of circulating substrate for the tightly regulated hydroxylation into the active, hormonal form of vitamin D (1,25OH2 D). The patients of this study were recruited in spring/summer because this period of the year is characterized by the highest values of vitamin D and to avoid the seasonal variation in response to different sunlight exposures. In this study of ED patients undergoing penile echo-color-Doppler, the mean vitamin D level was 21.3 ng/mL: 45.9% of the patient population was categorized as deficient in vitamin D, an additional 33.9% had vitamin D insufficiency, while only 20.2% had normal vitamin D levels. The high prevalence of vitamin D deficiency in our patients population is reflective of the generalized high prevalence rates of hypovitaminosis D in Europe [26]. In particular, in patients with severe/ complete ED the vitamin D level was significantly lower (P = 0.02) than in patients with mild ED. Penile echo-color-Doppler findings in our study revealed that A-ED patients showed more severe ED (IIEF-5 = 11) and lower level of vitamin D (18.2 ng/mL) in comparison with BL-ED (IIEF5 = 16, vitamin D = 22.5 ng/mL) and with NA-ED (IIEF-5 = 15, vitamin D = 25.3 ng/mL). Both vitamin D deficiency and vitamin D insufficiency had significantly higher frequency in A-ED than in NA-ED patients: 61.0% and 30.0% vs. 42.0% and 25.0%, respectively. The ED patients with vitamin D < 20.0 ng/mL showed more severe dysfunction (IIEF-5 = 12) in comparison with those with vitamin D > 20.0 ng/mL (IIEF-5 = 16) and to the first group belonged more patients with IIEF5 < 10: 38.59% and 25.3%, respectively. Most importantly, the group with vitamin D deficiency
5 was characterized by lower PSV (26 vs. 38) and a more prevalence of A-ED (45.6% vs. 22.3%) in comparison with group with vitamin D > 20.0 mg/mL indicating lower vascular endothelialdependent vasodilatation in the vitamin D deficient group compared with the vitamin D-non-deficient group. Clearly, the above results show that an association between vitamin D level and arteriogenic ED exists. No statistically significant differences were found regarding the laboratory parameters evaluated. In addition, the patients studied had no clinical evidence of atherosclerotic diseases and were free of the common risk factors associated with generalized penile arterial insufficiency such as hypertension, hyperlipidemia, cigarette smoking, diabetes mellitus, and pelvic irradiation. Despite of the good general status of health we found 35% of our ED patients with A-ED. We can explain this high prevalence with the “artery size” paradigm of Montorsi et al. [27]. Peripheral arterial disease caused by the gradual deposition of atherosclerotic plaques in the arterial system means limited blood supply to end organs. The different clinical presentation of symptoms is a consequence of the different size of the arteries supplying various end organs and is determined by the degree and percentage of luminal occlusion [28]. Building on the “artery size” paradigm, the various portions of the arterial tree are affected at different times and at different rates. According to this paradigm, 50% or more of the arterial lumen is affected before any arterial insufficiency is observed clinically [27]. A small plaque deposition or endothelial disturbance in the penile circulatory system is likely to present with ED symptoms, unlike in the coronary arteries where the burden of achieving 50% luminal occlusion means more plaque deposition and endothelial disturbance [27–29]. This usually takes several years to become clinically apparent. Endothelial dysfunction, characterized by impaired nitric oxide bioavailability and decreased vasodilation, precedes the development of atherosclerotic lesions and has been suggested as an important biological mechanism linking ED and cardiovascular diseases [30]. In fact, ED is often an expression of endothelial dysfunction. As a specialized vascular bed with smaller arterial diameter, the penile corpora may be more susceptible to systemic risk factors than the larger vessels in the heart and brain. In addition, the peripheral cavernosal arteries are end arteries and do not have the ability to form collaterals to compensate for decreased blood flow. Thus, loss of vasodilation may be recognized J Sex Med **;**:**–**
6 earlier in the microvascular penile bed than in coronary arteries. ED may appear years prior to clinical cardiovascular disease [31,32]. Studies have demonstrated direct relationships between ED and various components of the Metabolic Syndrome (MetS), including abdominal obesity, dyslipidemia, hyperglycemia, and elevated blood pressure [33–36]. Therefore, when these risk factors are clustered into a MetS, it is a logical hypothesis that it might represent an independent risk factor for ED. But our patients do not suffer of any of the abnormal metabolic conditions that characterize the MetS. In addition, circulating vitamin D levels have been associated with a risk of MetS in cross-sectional studies but not in longitudinal studies [37] and we need to have further randomized studies in order to determine whether vitamin D supplementation is effective for the prevention of metabolic syndrome. Several human studies have tested the hypothesis that patients with ED have systemic endothelial dysfunction, of which ED is the first clinical manifestation [31,38–40]. Despite differences in the patient populations and methods used to evaluate erectile and endothelial functions, results consistently showed an attenuation of peripheral, endothelium-dependent vasodilatation in patients with ED when compared with controls. It is worthy noting that both observational and interventional studies have established an association between vitamin D levels and endothelial dysfunction. Finally, two very recent studies suggested that low vitamin D level is an independent risk factor of endothelial dysfunction. In the first, Munisamy et al. found an impaired microvascular endothelial function in diabetic patients with deficient levels of vitamin compared with diabetic patients with nondeficient vitamin D levels [41]; in the second, Kumar Syal et al. found that endothelial dysfunction as assessed by brachial artery flow-mediated dilatation was more frequently observed among patients with angiographically documented coronary artery disease [42] in those with low vitamin D levels. Several mechanisms may explain impaired endothelial function in our patients with deficient vitamin D status. First, vitamin D affects endothelial function indirectly due to its renin suppression effect [43]. Renin suppression lessens the formation of angiotensin II and aldosterone, which consequently reduces BP. If vitamin D is insufficient, angiotensin II increases and markedly enhances nicotinamide adenine dinucleotide (phosphate) oxidase activity [44], resulting in the generation of J Sex Med **;**:**–**
Barassi et al. superoxide ions [45]. This free radical is able to deplete production of the vasodilator nitric oxide (NO) which may worsen endothelial function [46]. A typical pattern of oxidative stress in patients with A-ED compared with NA-ED subjects and healthy non-ED controls [47,48] was reported: i.e., a significant increase of reactive oxygen metabolites plasma levels and a simultaneous significant decrease in plasma total antioxidant status. Finally, it has been recently showed that vitamin D significantly reduced the endothelial malfunction and damage caused by oxidative stress, through the activation of mitogen-activated protein kinases/ extracellular signal-regulated kinases/sirtuin 1 axis [49]. Second, deficient vitamin D levels are likely to disrupt the NO pathway responsible for maintaining healthy vascular function. Third, vitamin receptor stimulation may influence a number of genes associated with endothelial function and regeneration. The vitamin D analogs calcitriol and paricalcitol were found to upregulate type-B endothelium receptors, which play a role in enhancing NO release and vessel relaxation [50]. We found only a modest correlation between vitamin D and PTH without a threshold in serum vitamin D, in keeping with several studies [51–53]. The classic inverse relationship between PTH and vitamin D concentrations suggests that the point for maximal PTH suppression by vitamin D occurs at approximately 30 mg/mL [54]. However, more recently the suppression value has been variable in different studies and is attributed to many factors [55,56]. A three-phase model suggests this might be explained by two thresholds of vitamin D rather than a single inflection point [57] and is complicated by several factors. In addition, variability in assays used to measure vitamin D [58] and PTH [59] also complicates the issue. In conclusion, in this study we demonstrated a higher presence of vitamin D deficiency in A-ED patients compared with NA-ED patients and a lower serum vitamin D levels in more severe ED patients. It is noteworthy that our subjects were asymptomatic and none reported the use of vitamin D supplements. Our study shows that, at least in our experimental conditions, the levels of vitamin D does not characterize only arteriogenic ED but all ED patients; moreover, also if significantly lower in A-ED are not sufficiently different to accurately discern between A-ED and NA-ED patients. Then, the low vitamin D levels may be an independent, potentially modifiable ED risk factor, particularly for dysfunction of arteriogenic etiology. It is probable that in conjunction with
Vitamin D and Erectile Dysfunction other risk factors, even where no clinical symptoms were present, the insufficiency/deficiency of vitamin D may be involved in the mechanism that promotes endothelial dysfunction causing ED. Finally, we suggest routine measurement of vitamin D in ED patients, with replacement therapy as required, like recently suggested [60]. In fact, we hypothesize that a level of vitamin D > 30 ng/mL could prevent the effect of the most common risk factors of ED like atherosclerosis, vascular calcification and endothelial dysfunction. Corresponding Author: Alessandra Barassi, MD, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Via di Rudinì 8, 20142 Milano, Italy. Tel: +393355444121; Fax: +3981844027; E-mail: [email protected] Conflict of Interest: The authors report no conflicts of interest. Statement of Authorship
Category 1 (a) Conception and Design Alessandra Barassi; Raffaele Pezzilli; Giovanni M. Colpi; Massimiliano M. Corsi Romanelli; Gian Vico Melzi d’Eril (b) Acquisition of Data Alessandra Barassi; Raffaele Pezzilli; Giovanni M. Colpi; Gian Vico Melzi d’Eril (c) Analysis and Interpretation of Data Raffaele Pezzilli; Alessandra Barassi; Gian Vico Melzi d’Eril
Category 2 (a) Drafting the Article Gian Vico Melzi d’Eril; Alessandra Barassi; Raffaele Pezzilli (b) Revising It for Intellectual Content Alessandra Barassi; Raffaele Pezzilli; Giovanni M. Colpi; Massimiliano M. Corsi Romanelli; Gian Vico Melzi d’Eril
Category 3 (a) Final Approval of the Completed Article Alessandra Barassi; Raffaele Pezzilli; Giovanni M. Colpi; Massimiliano M. Corsi Romanelli; Gian Vico Melzi d’Eril References 1 Ayta IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 1999;84:50–6. 2 Solomon H, Man JW, Jackson G. Erectile dysfunction and the cardiovascular patient: Endothelial dysfunction is the common denominator. Heart 2003;89:251–3.
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8 19 Paroni R, Barassi A, Ciociola F, Dozio E, Finati E, Fermo I, Ghilardi F, Colpi GM, Corsi MM, Melzi d’Eril GV. Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and L-arginine in patients with arteriogenic and non-arteriogenic erectile dysfunction. Int J Androl 2012;35: 660–7. 20 Dozio E, Barassi A, Dogliotti G, Malavazos AE, Colpi GM, D’Eril GV, Corsi MM. Adipokines, hormonal parameters, and cardiovascular risk factors: Similarities and differences between patients with erectile dysfunction of arteriogenic and nonarteriogenic origin. J Sex Med 2012;9:2370–7. 21 Dozio E, Barassi A, Dogliotti G, Malavazos AE, Colpi GM, Melzi D’Eril GV, Corsi Romanelli MM. Comment on: Adipokines, hormonal parameters, and cardiovascular risk factors: Similarities and differences between patients with erectile dysfunction of arteriogenic and nonarteriogenic origin. J Sex Med 2013;10:613. 22 Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 2008;88:582S–586S. 23 Dong Y, Stallmann-Jorgensen IS, Pollock NK, Harris RA, Keeton D, Huang Y, Li K, Bassali R, Guo DH, Thomas J, Pierce GL, White J, Holick MF, Zhu H. A 16-week randomized clinical trial of 2,000 international units daily vitamin D3 supplementation in black youth: 25-hydroxyvitamin D, adiposity, and arterial stiffness. J Clin Endocrinol Metab 2010; 95:4584–91. 24 Zittermann A. Vitamin D in preventive medicine: Are we ignoring the evidence? Br J Nutr 2003;89:552–72. 25 Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81. 26 Rosen CJ. Clinical practice. Vitamin D insufficiency. N Engl J Med 2011;364:248–54. 27 Montorsi P, Montorsi F, Schulman CC. Is erectile dysfunction the “tip of the iceberg” of a systemic vascular disorder? Eur Urol 2003;44:352–4. 28 Montorsi P, Ravagnani PM, Galli S, Rotatori F, Briganti A, Salonia A, Dehò F, Montorsi F. Common grounds for erectile dysfunction and coronary artery disease. Curr Opin Urol 2004;14:361–5. 29 Montorsi P, Ravagnani PM, Galli S, Salonia A, Briganti A, Werba JP, Montorsi F. Association between erectile dysfunction and coronary artery disease: Matching the right target with the right test in the right patient. Eur Urol 2006;50:721– 31. 30 Kaya C, Ergelen M, Iiktac A, Karaman MI. Impaired elasticity of aorta in patients with erectile dysfuntion. Urology 2007;70:558–62. 31 Chiurlia E, D’Amico R, Ratti C, Granata AR, Romagnoli R, Modena MG. Subclinical coronary artery atherosclerosis in patients with erectile dysfunction. J Am Coll Cardiol 2005;46:1503–6. 32 Thompson IM, Tangen CM, Goodman PJ, Probstfield JL, Moinpour CM, Coltman CA. Erectile dysfunction and subsequent cardiovascular disease. JAMA 2005;294:2996–3002. 33 Esposito K, Giugliano D. Obesity, the metabolic syndrome, and sexual dysfunction in men. Clin Pharmacol Ther 2011;90:169–73. 34 Roumeguere T, Wespes E, Carpentier Y, Hoffmann P, Schulman CC. Erectile dysfunction is associated with a high prevalence of hyperlipidemia and coronary heart disease risk. Eur Urol 2003;44:355–9. 35 Yang G, Pan C, Lu J. Prevalence of erectile dysfunction among Chinese men with type 2 diabetes mellitus. Int J Impot Res 2010;22:310–7. 36 Al-Hunayan A, Al-Mutar M, Kehinde EO, Thalib L, Al-Ghorory M. The prevalence and predictors of erectile dysfunction in men with newly diagnosed with type 2 diabetes mellitus. BJU Int 2007;99:130–4.
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Vitamin D and Erectile Dysfunction Alessandra Barassi, MD,* Raffaele Pezzilli, MD,† Giovanni M. Colpi, MD,‡ Massimiliano M. Corsi Romanelli, MD,§¶ and Gian Vico Melzi d’Eril, MD* *Clinical Biochemistry Laboratory, Department of Health Sciences, San Paolo Hospital, University of Milan, Milan, Italy; † Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant’Orsola-Malpighi Hospital, Bologna, Italy; ‡ ISES—Institute for the Infertility and Sexuality, Milan, Italy; §Department of Biomedical Science for Health, University of Milan, Milan, Italy; ¶Operative Unit of Laboratory Medicine, IRCCS Policlinico San Donato, Milan, Italy DOI: 10.1111/jsm.12661
ABSTRACT
Introduction. Endothelial dysfunction has been demonstrated to play an important role in pathogenesis of erectile dysfunction (ED) and vitamin D deficiency is deemed to promote endothelial dysfunctions. Aim. To evaluate the status of serum vitamin D in a group of patients with ED. Methods. Diagnosis and severity of ED was based on the IIEF-5 and its aetiology was classified as arteriogenic (A-ED), borderline (BL-ED), and non-arteriogenic (NA-ED) with penile-echo-color-Doppler in basal condition and after intracaversous injection of prostaglandin E1. Serum vitamin D and intact PTH concentrations were measured. Main Outcome Measures. Vitamin D levels of men with A-ED were compared with those of male with BL-ED and NA-ED. Results. Fifty patients were classified as A-ED, 28 as ED-BL and 65 as NA-ED, for a total of 143 cases. Mean vitamin D level was 21.3 ng/mL; vitamin D deficiency (<20 ng/mL) was present in 45.9% and only 20.2% had optimal vitamin D levels. Patients with severe/complete-ED had vitamin D level significantly lower (P = 0.02) than those with mild-ED. Vitamin level was negatively correlated with PTH and the correlation was more marked in subjects with vitamin D deficiency. Vitamin D deficiency in A-ED was significantly lower (P = 0.01) than in NA-ED patients. Penile-echo-color-Doppler revealed that A-ED (PSV ≤ 25 cm/second) was more frequent in those with vitamin D deficiency as compared with those with vitamin >20 ng/dL (45% vs. 24%; P < 0.05) and in the same population median PSV values were lower (26 vs. 38; P < 0.001) in vitamin D subjects. Conclusion. Our study shows that a significant proportion of ED patients have a vitamin D deficiency and that this condition is more frequent in patients with the arteriogenic etiology. Low levels of vitamin D might increase the ED risk by promoting endothelial dysfunction. Men with ED should be analyzed for vitamin D levels and particularly to A-ED patients with a low level a vitamin D supplementation is suggested. Barassi A, Pezzilli R, Colpi GM, Corsi Romanelli MM, and Melzi d’Eril GV. Vitamin D and erectile dysfunction. J Sex Med **;**:**–**. Key Words. Erectile Dysfunction; Vitamin D; Endothelial Dysfunctions
Introduction
E
rectile dysfunction (ED) is a highly prevalent global health problem with a considerable impact on the quality of life of middle-aged men. The projection for 2025 shows that over 322 million men will have ED [1]. Although nonvas-
© 2014 International Society for Sexual Medicine
cular diseases and conditions are closely related to ED [2], it is primarily a vascular disorder. Its most common cause is the arterial occlusion of atherosclerosis, which also affects the coronary arteries and can lead to a heart attack [3] or, in other parts of the body, vascular events such a stroke [4] and peripheral arterial disease [5]. J Sex Med **;**:**–**
2 Apart from its well-known role in bone and calcium metabolism, vitamin D deficiency has recently received widespread attention. In fact, vitamin D receptors and 1-alpha-hydroxylase, which converts vitamin D into the hormonal 1,25dihydroxyvitamin D form, are present in many tissues including endothelial cells [6]. In particular, vitamin D has recently been shown to modulate endothelial function [7]. In fact, endothelial cells synthesize vitamin D and express vitamin D receptors suggesting the hypothesis of a possible autocrine/intracrine mechanism exerted by vitamin D as a modulator of endothelial functions [8]. Observational data associate lower levels of serum vitamin D with coronary artery calcification, cardiovascular acute and chronic events, stroke and overall mortality [9–12]. In addition, it has been experimentally demonstrated that vitamin D deficiency, as well as excess, increases atherosclerotic calcification; the phenotype of vitamin D deficiency can be induced also before therapeutic measures for cardiovascular diseases associated with vitamin D deficiency and that maintenance of an optimal range of vitamin D signaling may be important for prevention of atherosclerotic calcification [13]. Furthermore, experimental studies showed beneficial vitamin D effects on cardiovascular risk factors, the heart and the blood vessels [14]. For all these reasons we evaluated the vitamin D levels in a group of men in good health with arteriogenic, nonarteriogenic and borderline ED, to assess the differences among the three ED subgroups before the presence of clinical or subclinical atherosclerotic symptoms. Investigation Protocol
In our center, patients complaining of ED are currently investigated by careful history-taking and clinical andrological examination; then, a few days later, by a panel of examinations, including blood tests, complete blood picture, hemoglobin, glycated hemoglobin, glucose, urea, creatinine, hs-PCR, total and HDL cholesterol, triglycerides, transaminases, testosterone, prolactin, 17-βestradiol, urine analysis and 24-hour urinary albumin excretion (microalbuminuria), the International Index of Erectile Function (IIEF) questionnaire and echo-color-Doppler of both cavernous arteries. The IIEF questionnaire is a validated, self-administered tool [15,16], but we only evaluated the answers to the first five (erectile response dominium, IIEF-5) of the 15 questions. Possible scores for the IIEF-5 range from 5 to 25; J Sex Med **;**:**–**
Barassi et al. scores of 22–25 indicate normal erectile function whereas scores of 21 or below indicate ED (mild 16–20, moderate 11–15, severe 5–10, complete ≤ 4) [15]. Penile echo-color-Doppler was performed in basal conditions and after an intracavernous injection of 10 μg prostaglandin E1 (PgE1) [17], and the peak systolic velocity (PSV) and end-diastolic velocity (EDV) were recorded at 5, 10, 15, 20, and 25 minutes after the injection in the proximal portion of the penis. Patients were classified as “arteriogenic” (A-ED) when their PSV was <25 cm/second, “borderline” (BL-ED) with PSV between 25 and 35 cm/second and “nonarteriogenic” (NA-ED) when their PSV was ≥35 cm/second, or ≤35 cm/second but >25 cm/second with concomitant EDV ≤ 0 cm/second [18,19]. If a patient appeared stressed, he was given a second injection of the same dose of PgE1 and all measurements were repeated. The erection quality was estimated 20 minutes after each injection. From 30 to 60 minutes before the penile echocolor-Doppler, participants were placed in a supine position and blood samples were drawn from a cubital vein into EDTA tubes. Samples were centrifuged at 3,000 rpm for 10 minutes. The serum was separated and stored at −80°C until analysis. Patients
The patients included in the study were outpatients complaining of ED consecutively attending our Andrology Unit, Ospedale San Paolo, Milan, in the period May 2011-September 2011 and May 2012September 2012. Out of these ED patients, 50 were classified as arteriogenic (A-ED), 28 as border-line (BL-ED) and 65 as non-arteriogenic (NA-ED) patients, for a total of 143 cases (median age 47 years, range 30–60). The exclusion criteria were the following: age less than 30 years and over 60 years, clinical evidence of congestive heart failure, renal insufficiency, anemia, acute infection or rheumatic diseases within 2 months; clinical evidence from the patient’s clinical history of coronary artery disease, hypertension (>140/90 mm Hg in three consecutive recordings at rest), malignancy, systemic inflammatory disease, hepatopathies or arrhythmias, current smoking, and vitamin supplementation or chronic drug assumption. The patients of the three ED subgroups declared normal physical activity and not to take statins. All patients were referred to a cardiologist for evaluation of ischemic heart disease (IHD). The evaluation consisted of a comprehensive clinical history, physical examination, and resting electro-
3
Vitamin D and Erectile Dysfunction cardiogram. The diagnosis of IHD relied on the detection of a 1-mm or more horizontal od downsloping ST segment depression, frequent ventricular premature beats, or typical chest pain during the exercise treadmill test. This investigation conforms to the principles outlined in the Declaration of Helsinki. Signed informed written consent was obtained from all subjects before their participation in the study. No ethical committee approval was required because no additional blood was needed for this study and this was explained thoroughly to all patients who gave their written informed consent also for laboratory tests and also because this procedure has been reported to be acceptable [20,21].
Assays HbA1c was measured using a high performance liquid chromatography (HPLC) method (Bio-Rad, Italy). Plasma glucose, creatinine, urea, total cholesterol, HDL-cholesterol, triglycerides, ALT, AST, prolactin, testosterone and 17-β-estradiol were analyzed with commercially available kits using Modular EVO (Roche, Monza, Italy). Plasma LDL-cholesterol was calculated with the use of Friedewald’s formula. Urinary microalbumin concentration was measured in duplicate in the morning samples on a Behring Nephelometer II analyzer (Siemens, Milan, Italy). In this study serum 25-hydroxyvitamin D was measured to assess vitamin D status as it has a long circulating half-life of approximately 15 days [22]. Serum 25-hydroxyvitamin D levels were measured using by radioimmunoassay (RIA) double antibody assay (DiaSorin, Saluggia, Italy). Within-run coefficient of variation (CV) was 8.6–12.5% and total imprecision CV was 8.2–11.0%; the detection limit of the assay was 1.5 ng/mL. Concentration of vitamin D < 20.0 ng/mL (<50.0 nmol/L) is adopted as “deficient” and between 20.0 to 30.0 ng/mL as “insufficient” while optimal levels were defined as vitamin D > 30.0 ng/mL [23–25]. Serum PTH levels were measured using 1–84 PTH chemiluminescence immunoassay (DiaSorin, Italy). Within-run CV was ≤6% and between-run CV was ≤9%; the detection limit of the assay was 1.5 ng/mL. Statistical Analysis Data are reported as median and range or absolute number and the relative frequency. For statistical analysis the Mann–Whitney U-test was used to compare data between the groups, the Wilcoxon
test for paired data to analyze the correlation between vitamin D and PTH, and the chi-squared test to compare the frequencies between the groups. P values < 0.05 were considered statistically significant. All analyses were carried out by using the SPSS 13.0 statistical package (SPSS Inc., Chicago, IL, USA).
Results
In the ED patients of this study the median IIEF-5 value was 14.0 and the vitamin D level (median, range in ng/mL) was 21.3, 5.7–52.9. Vitamin D deficiency was present in 45.9%, with insufficiency in 33.9%, while only 20.2% had optimal levels. Severe vitamin D deficiency (<10.0 ng/mL) was observed in 5.6% patients. There was a significant difference (P = 0.02) between vitamin D levels in patients with IIEF-5 16–20 (mild ED) and IIEF5 ≤ 10 (severe/complete ED) that were 26.1 (range 11.8–52.9) ng/mL and 19.8 (range 5.7–45.4) ng/mL, respectively. In the patients of this study, vitamin D was negatively associated with PTH (r = −0.57; P < 0.001). The negative association between vitamin D and PTH was more marked in subjects with vitamin D < 20.0 ng/mL (r = −0.58; P < 0.0001) compared with those with levels >30.0 ng/mL (r = −0.079; P = 0.71). Of the 143 men included in the study, 50 patients (35.0%) were classified as having A-ED, 28 patients (19.6%) as having BL-ED and 65 patients (45.4%) as having NA-ED. In A-ED (median age 48; 33–60 years), BL-ED (median age 45; 30–60 years) and NA-ED (median age 46; 31–60 years) the mean of IIEF values were 11 (1–20), 16 (6–20) and 15 (2–21), respectively. Table 1 shows physical and biochemical parameters of the patients in this study. Vitamin D levels in A-ED patients (18.2, 5.7– 38.0) were significantly lower (P = 0.04) than in BL-ED patients (22.5, 10.2–31.4) and (P = 0.01) than in NA-ED patients (25.3, 6.5–52.9), but no difference (P = 0.50) was observed between the levels of vitamin D among BL-ED and NA-ED patients. Furthermore, 30.0% (n = 15) and 61.0% (n = 30) of A-ED, 25.0% (n = 7) and 30.0% (n = 8) of BL-ED, 25.0% (n = 16) and 42.0% (n = 27) of NA-ED, have levels of vitamin D between 20.0 and 29.0 ng/mL and <20.0 ng/mL, respectively. No statistically significant differences (P > 0.05) were found in the three groups regarding the other laboratory parameters evaluated (i.e., creatinine, glucose, ALT, AST, total cholesterol, HDL choJ Sex Med **;**:**–**
4 Table 1
Barassi et al. Clinical and laboratory features of patients with erectile dysfunction
Patients data Age (years) IIEF-5 score PSV Body mass index (kg/m2) Laboratory evaluation Study parameters Vitamin D (pg/mL) Other parametres Creatinine (mg/dL) Glucose (mg/dL) Calcium (mg/dL) ALT (U/L) AST (U/L) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Triglycerides (mg/dL) HbA1c (%) 17-β-estradiol (pg/mL) Prolactin (ng/mL) Testosterone (ng/mL)
A-ED (n = 50)
BL-ED (n = 28)
NA-ED (n = 65)
48 (33–60) 11 (1–20) 20 (8–24)* 23.8 (19.8–25.6)
45 (30–60) 16 (6–20) 31 (24–36) 24.3 (21.5–25.9)
46 (31–60) 15 (2–21) 45 (37–99)** 23.2 (21.5–26.2)
18.2 (5.7–38.0)***
22.5 (10.2–31.4)
25.3 (6.5–52.9)
0.90 (0.55–1.25) 92 (51–109) 9.1 (8.5–9.6) 23 (10–59) 23 (13–63) 200 (113–240) 50 (30–88) 133 (91–153) 103 (48–255) 5.7 (4.8–6.4) 27.5 (11.1–46.6) 9.1 (2.2–28.7) 410 (211–590)
0.97 (0.8–1.13) 95 (75–110) 9.2 (8.4–9.7) 24 (12–65) 27 (14–53) 204 (128–230) 47 (26–87) 129 (90–156) 107 (43–245) 5.5 (4.1–6.3) 25.4 (10–52.3) 9.3 (2.6–29.2) 470 (250–605)
0.90 (0.60–1.80) 90 (58–110) 9.3 (8.5–9.8) 27 (6–76) 27 (10–76) 198 (141–251) 52 (30–94) 125 (95–137) 98 (54–220) 5.3 (4.5–6.2) 22.8 (10–45.8) 8.6 (1.1–21.3) 454 (220–616)
Note: Values are reported as median and range. *P < 0.001 vs. BL-ED and NA-ED **P < 0.001 vs. BL-ED ***P < 0.04 vs. BL-ED and P < 0.01 vs. NA-ED A-ED = arteriogenic erectile dysfunction; BL-ED = borderline arteriogenic erectile dysfunction; NA-ED = non-arteriogenic erectile dysfunction
lesterol, LDL cholesterol, triglycerides, HbA1c, 17-β-estradiol, prolactin and testosterone) (Table 1). On categorizing patients into two groups those with vitamin D deficiency and those without (Table 2) there was no significant difference
Table 2
between the two groups in terms of clinical and metabolic parameters. Patients with severe/ complete ED (IIEF-5 ≤ 10) were more frequent in the group with vitamin D levels <20.0 ng/mL as compared with those in the group with levels >20.0 ng/mL (38.6% vs. 25.3%). Then, there was
Characteristics of patients with and without vitamin D deficiency
Patients data Age (years) IIEF-5 score PSV Body mass index (kg/m2) Laboratory evaluation Creatinine (mg/dL) Glucose (mg/dL) Calcium (mg/dL) ALT (U/L) AST (U/L) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Triglycerides (mg/dL) HbA1c (%) 17-β-estradiol (pg/mL) Prolactin (ng/mL) Testosterone (ng/mL) Note: Values are reported as median and range.
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Vit D < 20 ng/mL
Vit D > 20 ng/mL
P value
47 (35–60) 12 (1–24) 26 (8–55) 23.8 (21.2–26.2)
46 (30–60) 16 (1–25) 38 (11–99) 22.9 (19.8–25.5)
NS P = 0.008 P < 0.001 NS
0.90 (0.55–1.80) 92 (51–110) 9.1 (8.4–9.5) 27 (10–65) 23 (13–44) 204 (113–240) 51 (37–94) 136 (93–156) 110 (48–255) 5.6 (4.1–6.0) 26 (10–46.6) 10 (3.6–18.6) 430 (220–585)
0.91 (0.60–1.32) 89 (57–103) 9.4 (8.5–9.8) 26 (10–76) 23 (10–63) 199 (135–251) 50 (30–86) 128 (90–141) 99 (43–177) 5.7 (4.8–6.4) 25 (10–52.3) 9 (3.3–29.2) 470 (260–616)
NS NS NS NS NS NS NS NS NS NS NS NS NS
Vitamin D and Erectile Dysfunction a trend toward lower mean vitamin D levels with increasing severity of ED, but this was not statistically significant. However, the median level of IIEF-5 was significantly lower in those with lower vitamin D levels 12 (range 1–24) vs. 16 ([range 1–25]; P = 0.008). In the same two groups there were significantly lower median PSV values with decreasing vitamin D levels. Median PSV values were 26 (8–55) vs. 38 (11–99), respectively for the two groups (P < 0.001). The prevalence of PSV values < 25 (A-ED) was 45.6% vs. 23.9%, respectively, in patients with vitamin D levels <20.0 ng/ mL, and >20.0 ng/mL (P < 0.05). Discussion
Vitamin D (25-hydroxyvitamin D) is considered to be the best indicator of overall vitamin D status of an individual and to reflect the level of circulating substrate for the tightly regulated hydroxylation into the active, hormonal form of vitamin D (1,25OH2 D). The patients of this study were recruited in spring/summer because this period of the year is characterized by the highest values of vitamin D and to avoid the seasonal variation in response to different sunlight exposures. In this study of ED patients undergoing penile echo-color-Doppler, the mean vitamin D level was 21.3 ng/mL: 45.9% of the patient population was categorized as deficient in vitamin D, an additional 33.9% had vitamin D insufficiency, while only 20.2% had normal vitamin D levels. The high prevalence of vitamin D deficiency in our patients population is reflective of the generalized high prevalence rates of hypovitaminosis D in Europe [26]. In particular, in patients with severe/ complete ED the vitamin D level was significantly lower (P = 0.02) than in patients with mild ED. Penile echo-color-Doppler findings in our study revealed that A-ED patients showed more severe ED (IIEF-5 = 11) and lower level of vitamin D (18.2 ng/mL) in comparison with BL-ED (IIEF5 = 16, vitamin D = 22.5 ng/mL) and with NA-ED (IIEF-5 = 15, vitamin D = 25.3 ng/mL). Both vitamin D deficiency and vitamin D insufficiency had significantly higher frequency in A-ED than in NA-ED patients: 61.0% and 30.0% vs. 42.0% and 25.0%, respectively. The ED patients with vitamin D < 20.0 ng/mL showed more severe dysfunction (IIEF-5 = 12) in comparison with those with vitamin D > 20.0 ng/mL (IIEF-5 = 16) and to the first group belonged more patients with IIEF5 < 10: 38.59% and 25.3%, respectively. Most importantly, the group with vitamin D deficiency
5 was characterized by lower PSV (26 vs. 38) and a more prevalence of A-ED (45.6% vs. 22.3%) in comparison with group with vitamin D > 20.0 mg/mL indicating lower vascular endothelialdependent vasodilatation in the vitamin D deficient group compared with the vitamin D-non-deficient group. Clearly, the above results show that an association between vitamin D level and arteriogenic ED exists. No statistically significant differences were found regarding the laboratory parameters evaluated. In addition, the patients studied had no clinical evidence of atherosclerotic diseases and were free of the common risk factors associated with generalized penile arterial insufficiency such as hypertension, hyperlipidemia, cigarette smoking, diabetes mellitus, and pelvic irradiation. Despite of the good general status of health we found 35% of our ED patients with A-ED. We can explain this high prevalence with the “artery size” paradigm of Montorsi et al. [27]. Peripheral arterial disease caused by the gradual deposition of atherosclerotic plaques in the arterial system means limited blood supply to end organs. The different clinical presentation of symptoms is a consequence of the different size of the arteries supplying various end organs and is determined by the degree and percentage of luminal occlusion [28]. Building on the “artery size” paradigm, the various portions of the arterial tree are affected at different times and at different rates. According to this paradigm, 50% or more of the arterial lumen is affected before any arterial insufficiency is observed clinically [27]. A small plaque deposition or endothelial disturbance in the penile circulatory system is likely to present with ED symptoms, unlike in the coronary arteries where the burden of achieving 50% luminal occlusion means more plaque deposition and endothelial disturbance [27–29]. This usually takes several years to become clinically apparent. Endothelial dysfunction, characterized by impaired nitric oxide bioavailability and decreased vasodilation, precedes the development of atherosclerotic lesions and has been suggested as an important biological mechanism linking ED and cardiovascular diseases [30]. In fact, ED is often an expression of endothelial dysfunction. As a specialized vascular bed with smaller arterial diameter, the penile corpora may be more susceptible to systemic risk factors than the larger vessels in the heart and brain. In addition, the peripheral cavernosal arteries are end arteries and do not have the ability to form collaterals to compensate for decreased blood flow. Thus, loss of vasodilation may be recognized J Sex Med **;**:**–**
6 earlier in the microvascular penile bed than in coronary arteries. ED may appear years prior to clinical cardiovascular disease [31,32]. Studies have demonstrated direct relationships between ED and various components of the Metabolic Syndrome (MetS), including abdominal obesity, dyslipidemia, hyperglycemia, and elevated blood pressure [33–36]. Therefore, when these risk factors are clustered into a MetS, it is a logical hypothesis that it might represent an independent risk factor for ED. But our patients do not suffer of any of the abnormal metabolic conditions that characterize the MetS. In addition, circulating vitamin D levels have been associated with a risk of MetS in cross-sectional studies but not in longitudinal studies [37] and we need to have further randomized studies in order to determine whether vitamin D supplementation is effective for the prevention of metabolic syndrome. Several human studies have tested the hypothesis that patients with ED have systemic endothelial dysfunction, of which ED is the first clinical manifestation [31,38–40]. Despite differences in the patient populations and methods used to evaluate erectile and endothelial functions, results consistently showed an attenuation of peripheral, endothelium-dependent vasodilatation in patients with ED when compared with controls. It is worthy noting that both observational and interventional studies have established an association between vitamin D levels and endothelial dysfunction. Finally, two very recent studies suggested that low vitamin D level is an independent risk factor of endothelial dysfunction. In the first, Munisamy et al. found an impaired microvascular endothelial function in diabetic patients with deficient levels of vitamin compared with diabetic patients with nondeficient vitamin D levels [41]; in the second, Kumar Syal et al. found that endothelial dysfunction as assessed by brachial artery flow-mediated dilatation was more frequently observed among patients with angiographically documented coronary artery disease [42] in those with low vitamin D levels. Several mechanisms may explain impaired endothelial function in our patients with deficient vitamin D status. First, vitamin D affects endothelial function indirectly due to its renin suppression effect [43]. Renin suppression lessens the formation of angiotensin II and aldosterone, which consequently reduces BP. If vitamin D is insufficient, angiotensin II increases and markedly enhances nicotinamide adenine dinucleotide (phosphate) oxidase activity [44], resulting in the generation of J Sex Med **;**:**–**
Barassi et al. superoxide ions [45]. This free radical is able to deplete production of the vasodilator nitric oxide (NO) which may worsen endothelial function [46]. A typical pattern of oxidative stress in patients with A-ED compared with NA-ED subjects and healthy non-ED controls [47,48] was reported: i.e., a significant increase of reactive oxygen metabolites plasma levels and a simultaneous significant decrease in plasma total antioxidant status. Finally, it has been recently showed that vitamin D significantly reduced the endothelial malfunction and damage caused by oxidative stress, through the activation of mitogen-activated protein kinases/ extracellular signal-regulated kinases/sirtuin 1 axis [49]. Second, deficient vitamin D levels are likely to disrupt the NO pathway responsible for maintaining healthy vascular function. Third, vitamin receptor stimulation may influence a number of genes associated with endothelial function and regeneration. The vitamin D analogs calcitriol and paricalcitol were found to upregulate type-B endothelium receptors, which play a role in enhancing NO release and vessel relaxation [50]. We found only a modest correlation between vitamin D and PTH without a threshold in serum vitamin D, in keeping with several studies [51–53]. The classic inverse relationship between PTH and vitamin D concentrations suggests that the point for maximal PTH suppression by vitamin D occurs at approximately 30 mg/mL [54]. However, more recently the suppression value has been variable in different studies and is attributed to many factors [55,56]. A three-phase model suggests this might be explained by two thresholds of vitamin D rather than a single inflection point [57] and is complicated by several factors. In addition, variability in assays used to measure vitamin D [58] and PTH [59] also complicates the issue. In conclusion, in this study we demonstrated a higher presence of vitamin D deficiency in A-ED patients compared with NA-ED patients and a lower serum vitamin D levels in more severe ED patients. It is noteworthy that our subjects were asymptomatic and none reported the use of vitamin D supplements. Our study shows that, at least in our experimental conditions, the levels of vitamin D does not characterize only arteriogenic ED but all ED patients; moreover, also if significantly lower in A-ED are not sufficiently different to accurately discern between A-ED and NA-ED patients. Then, the low vitamin D levels may be an independent, potentially modifiable ED risk factor, particularly for dysfunction of arteriogenic etiology. It is probable that in conjunction with
Vitamin D and Erectile Dysfunction other risk factors, even where no clinical symptoms were present, the insufficiency/deficiency of vitamin D may be involved in the mechanism that promotes endothelial dysfunction causing ED. Finally, we suggest routine measurement of vitamin D in ED patients, with replacement therapy as required, like recently suggested [60]. In fact, we hypothesize that a level of vitamin D > 30 ng/mL could prevent the effect of the most common risk factors of ED like atherosclerosis, vascular calcification and endothelial dysfunction. Corresponding Author: Alessandra Barassi, MD, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Via di Rudinì 8, 20142 Milano, Italy. Tel: +393355444121; Fax: +3981844027; E-mail: [email protected] Conflict of Interest: The authors report no conflicts of interest. Statement of Authorship
Category 1 (a) Conception and Design Alessandra Barassi; Raffaele Pezzilli; Giovanni M. Colpi; Massimiliano M. Corsi Romanelli; Gian Vico Melzi d’Eril (b) Acquisition of Data Alessandra Barassi; Raffaele Pezzilli; Giovanni M. Colpi; Gian Vico Melzi d’Eril (c) Analysis and Interpretation of Data Raffaele Pezzilli; Alessandra Barassi; Gian Vico Melzi d’Eril
Category 2 (a) Drafting the Article Gian Vico Melzi d’Eril; Alessandra Barassi; Raffaele Pezzilli (b) Revising It for Intellectual Content Alessandra Barassi; Raffaele Pezzilli; Giovanni M. Colpi; Massimiliano M. Corsi Romanelli; Gian Vico Melzi d’Eril
Category 3 (a) Final Approval of the Completed Article Alessandra Barassi; Raffaele Pezzilli; Giovanni M. Colpi; Massimiliano M. Corsi Romanelli; Gian Vico Melzi d’Eril References 1 Ayta IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 1999;84:50–6. 2 Solomon H, Man JW, Jackson G. Erectile dysfunction and the cardiovascular patient: Endothelial dysfunction is the common denominator. Heart 2003;89:251–3.
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