Vitamin D and Endothelial Function: Comparison
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Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Andrea Crafa.

Vitamin D deficiency (VDD) and erectile dysfunction (ED) heavily burden the male population. The higher prevalence of both conditions in the elderly suggests a possible relationship between the two conditions. In addition, in vitro, animal, and human studies have revealed several mechanisms that may relate VDD to ED. The main mechanism by which vitamin D might exert its action on sexual function appears to be through the regulation of endothelial function. Indeed, VDD correlates with several markers of endothelial function. The action of vitamin D on the endothelium would be exercised both indirectly through its intervention in inflammatory processes and through the production of oxygen free radicals, and directly through the regulation of vascular stiffness, the production of nitric oxide, and the regulation of vessel permeability.

  • vitamin D
  • vitamin D deficiency
  • erectile dysfunction

1. Introduction

Erectile dysfunction (ED) is the inability to achieve or maintain sufficient penile stiffness for satisfactory sexual intercourse and is a leading cause of sexual dysfunction affecting hundreds of millions of men worldwide [1]. It negatively influences interpersonal relationships and the quality of life of affected men and their partners [2]. It also causes a significant economic burden, as ED patients have decreased productivity at work even when controlling for potential confounders [3]. Epidemiologic studies regarding the prevalence of ED have demonstrated a strong positive association between this condition and age [4]. Indeed, an umbrella review of 98 meta-analyses reported a prevalence of approximately 20% in men younger than 30 years of age, 25% in men 30–39 years of age, 40% in 40–49 years of age, 60% among 50–59-year-olds, 80% in 60–69 year-olds, and 90% in men over 70 years old [5].
The pathophysiology of ED depends on an alteration of the psychosocial and organic physiologic factors that occur in a normal erection. In a normal physiologic erection, nitric oxide (NO) released from the endothelium and nerve terminals causes cavernous and arterial smooth muscle relaxation. The resulting arterial dilation increases the flow to the cavernous sinusoids, which compress the emissary veins within the rigid tunica albuginea [6]. Therefore, a reduction in NO production or sensitivity may cause ED. For example, in vasculogenic ED, endothelial dysfunction due to vascular disease reduces endothelial NO levels and sensitivity to this signaling molecule [7].
ED can be broadly classified as organic or psychogenic, but most cases have both components [8]. Vasculogenic ED is the most common cause of organic ED and is particularly prevalent in older men and those with risk factors for heart and vascular disease such as hypertension, dyslipidemia, diabetes mellitus (DM), atherosclerosis, obesity, cigarette smoking, and other cardiovascular disorders [8].
Vitamin D is a steroid hormone and vitamin that plays a critical role in regulating calcium-phosphorous homeostasis and affects the proper functioning of multiple organ systems [9]. The Endocrine Society defines vitamin D deficiency (VDD) as a 25-hydroxyvitamin D [25(OH)D] level below 20 ng/mL and insufficiency as a level between 21 and 29 ng/mL [10].
Hypovitaminosis D has an estimated prevalence of 20–100% among elderly men and women in the United States, Canada, and Europe [11]. Regarding ED, age and vitamin D levels have been linked, with increasing age being associated with reduced vitamin D levels and increased risk of hypovitaminosis D [12]. This is probably due to the decreased capacity of aging skin to produce cholecalciferol, a precursor to 25(OH)D and fully active 1α,25-dihydroxy vitamin D3 [1,25(OH)2D3] [12].
Other risk factors for VDD are related to ultraviolet-mediated production of vitamin D or dietary intake of vitamin D. In healthy adult men, these risk factors include decreased outdoor activities, excessive sunscreen, and reduced consumption of vitamin D-fortified milk [9]. Dark-skinned people are also at a higher risk due to the increased absorption of ultraviolet B by melanin [13].
The age dependence of hypovitaminosis D and ED seems to suggest a possible relationship between the two conditions. Consistent with this theory, it was observed that in patients older than 60 years with moderate to severe ED and lower urinary tract symptoms (LUTS), 25(OH)D levels and VDD were the independent risk factors for ED in the multivariate regression analysis, whereas these associations were not observed in analyses performed in other subgroups according to age and LUTS severity [14].
Many possible mechanisms linking VDD and ED have been proposed. In detail, the effect of VDD on endothelial function, the role of VD in the upregulation of NO synthase (NOS), the increase in the degree of inflammation, and the possible endocrinological dysregulation due to VDD are among the main mechanisms involved [15].
Several studies have shown a link between decreased vitamin D levels and ED. One study found that a significant proportion of ED patients have VDD, particularly among patients with arteriogenic ED, as assessed by penile Doppler ultrasound [16]. Wu and colleagues echoed these results by demonstrating that serum levels of 25(OH)D were related to ED severity and vasodilation function [17]. Another study also established the association between VDD and the prevalence of ED independent of atherosclerotic cardiovascular disease (CVD) risk factors. However, this study assessed ED with a self-reported response to a single question. However, the subjective assessment of ED by answering a single question is a major limitation of this study [18].
Meta-analytic studies on this topic seem to confirm this association. Indeed, in a meta-analysis of seven studies, it was observed that vitamin D levels were higher in patients without ED than in those with ED. Furthermore, the presence of VDD correlated with lower scores of the International Index of Erectile Function (IIEF)-5 scores [19]. Similarly, another meta-analysis of eight studies showed a relationship between VDD and ED severity as measured by the IIEF-5 questionnaire [20]. It should be considered, however, that both meta-analyses include studies with high heterogeneity due to the different populations involved and also to the different methods of vitamin D measurement that could influence the results [19,20][19][20].
All these studies suggest VDD could be an independent risk factor for organic ED, although more intervention studies are needed to better establish a true link between these two conditions.

2. Vitamin D and Endothelial Function

The association between ED and CVD is very close. Indeed, more than 70% of patients with CVD (including coronary artery disease, cerebrovascular disease, and peripheral artery disease) have ED [21]. Furthermore, according to the artery size theory (small size of the cavernous arteries compared to other vascular districts), ED may only be the “tip of the iceberg” of chronic vascular disease and could represent its first manifestation [22]. Consequently, the onset of ED would precede the onset of major cardiovascular events by up to several years, proving to be a low-cost biomarker for the diagnosis and prevention of CVD [21]. The close association between ED and CVD is also demonstrated by the common risk factors between the two conditions (obesity, DM, hypercholesterolemia, and hypertension). Furthermore, both conditions share endothelial dysfunction as the main pathogenic mechanism [21]. Several mechanisms contribute to the genesis of endothelial dysfunction, such as the reduced activity of endothelial NOS (eNOS) enzyme and, therefore, NO production, increased levels of reactive oxygen species (ROS) and pro-inflammatory cytokines (IL 1, TNFα), increased vascular permeability, increased vascular stiffness, and inability to regenerate from endothelial progenitor cells (EPC) [23]. Testosterone levels also play a role in this context. In fact, this hormone seems to regulate NO production, the stiffness of the vessels, and the production of inflammatory cytokines. Furthermore, hormone deficiency is associated with greater severity of the atherosclerotic process [23]. In agreement, low testosterone levels have been observed to play a predictive role in cardiovascular mortality and morbidity [24]. Vitamin D would appear to have a regulatory role in endothelial function by intervening in many of the mechanisms mentioned above, including the production of testosterone. Furthermore, meta-analytical studies have observed an inverse correlation between 25(OH)D levels and cardiovascular risk, reinforcing the hypothesis of the role of this vitamin in proper vascular function [25,26][25][26]. The association between vitamin D and endothelial function is also highlighted by the correlation between vitamin D levels and some markers of endothelial dysfunction. For example, a correlation has been observed between vitamin D levels and mean platelet volume (MPV) [27]. This correlation between platelets and vitamin D is not surprising since the vitamin D receptor (VDR) is expressed at the mitochondrial level in human platelets, suggesting that this hormone may play a role in platelet differentiation and function [28]. MPV, in turn, correlates with increased cardiovascular risk and ED, as larger platelets show greater reactivity and thrombogenicity [29]. In agreement, a study of 78 patients with stable coronary artery disease, divided into three subgroups according to vitamin D levels, observed higher MPV values in patients with more severe VDD, suggesting that the regulation of thrombosis, hemostatic processes, and platelet function is another mechanism by which vitamin D affects cardiovascular function [30]. Similarly, another study of 90 patients with ED reported that the severity of ED (evaluated by the IIEF-EF questionnaire containing six items) correlates with lower vitamin D levels and that, in turn, patients with severe ED have higher MPV values. The correlation analysis showed that vitamin D levels correlated negatively with MPV values, reinforcing the hypothesis of a relationship between these two parameters [31]. Another marker of endothelial dysfunction closely associated with the presence of ED is EPC. These cells are involved in the repair of endothelial damage and have been considered progenitor cells that are found in high numbers in patients with arterial ED [32]. In this context, vitamin D has been shown to play a protective role in EPCs, probably through the inhibition of inflammation. Furthermore, it would seem to favor the correct process of migration and adhesion of these cells, thus facilitating the restoration of the integrity of the endothelial barrier [33]. Moreover, another in vitro study showed that incubation with vitamin D increases the angiogenic and, therefore, the reparative capacity of EPCs, probably by increasing vascular endothelial growth factor and pro-metalloproteinase-2, two key factors for correct angiogenesis [34]. Another marker closely associated with the previous one is the endothelial microparticles (EMPs). These are released into the circulation by endothelial cells, and their quantity is significantly higher when the endothelium is dysfunctional. Once in circulation, EMPs have pro-inflammatory and procoagulant effects, which facilitate the progression of vascular damage [35]. Among the mechanisms believed to be related to endothelial dysfunction is the increased production of ROS [36]. In vitro incubation with calcitriol was observed to prevent EMP formation from endothelial cells exposed to increased oxidative stress, probably through an increase in eNOS expression and inhibition of Rho-associated coiled-coil protein kinase 1, a key regulator of actin–myosin contraction, which appears to be abnormally expressed in patients with endothelial dysfunction and CVD [36]. Furthermore, vitamin D also seems to exert a direct antioxidant effect due to the reduction of H2O2 through the modulation of monoamine oxidases and pro-oxidant enzymes of the nitrogen oxides family [37]. Another marker of endothelial dysfunction is endothelial cell-specific molecule-1 (ENDOCAN), which is associated with systemic inflammation, DM, atherosclerosis, hypertension, and acute coronary syndrome [38]. Levels of this marker are associated with worse peak systolic velocity on dynamic penile echo color Doppler in patients with ED, and this correlates with the severity of the condition [38]. Again, vitamin D may play a role, as in healthy men, low vitamin D levels have been associated with elevated ENDOCAN levels, suggesting that VDD may contribute to endothelial damage [39]. Furthermore, vitamin D supplementation was associated with a reduction in ENDOCAN levels in patients undergoing kidney transplants, suggesting its role as therapy in reducing endothelial dysfunction [40]. Other evidence in favor of the role of vitamin D on endothelial function comes from studies that evaluated its relationship with other markers of endothelial health, such as carotid artery intima–media thickness (CIMT) [41], ankle–brachial index [42], and flow-mediated dilation (FMD) [43]. The latter is closely linked to endothelial function and is significantly reduced in patients affected by vascular diseases [43]. Consequently, a study of 100 men (50 with acute myocardial infarction (MI) and 50 age-matched healthy controls) observed that FMD and vitamin D levels were markedly reduced in patients with MI compared with controls. Furthermore, the results of this study showed the presence of a positive correlation between vitamin D levels and FMD [43]. Another double-blind randomized clinical study of 44 hypertensive and type 2 diabetic patients divided into two groups, with 23 patients treated with 2000 IU of cholecalciferol daily for 12 weeks and 21 with placebo for 12 weeks, showed that FMD increased significantly in the vitamin D-treated group. Furthermore, these patients also showed a significant reduction in oxidized LDL levels. Therefore, this study would confirm the role of vitamin D in the reduction of endothelial dysfunction [44]. Similarly, an association was observed between vitamin D levels, CIMT, and ED, suggesting that the assessment of vitamin D levels may be useful in the diagnosis of ED and that its supplementation may play a role in therapeutic management [41]. In addition to acting on the endothelium by promoting NO production, reducing platelet aggregation, modulating the coagulation cascade by reducing tissue factor levels, and upregulating thrombomodulin and antithrombin, vitamin D also counteracts inflammation [45]. This, in turn, is one of the main mechanisms of endothelial dysfunction and the atherosclerotic process [23]. In detail, vitamin D can regulate the function of both innate and adaptive immune responses. For the innate response, it regulates antigen-presenting dendritic cells, promoting the formation of immature dendritic cells that express fewer major histocompatibility complex (MHC) class II molecules and costimulatory molecules and are therefore less able to present the antigen. This is associated with decreased IL12 production and increased IL10 expression resulting in modulation of the immune response [46]. Regarding the adaptive response, vitamin D seems to favor the transition from a Th1 inflammatory response to a Th2 anti-inflammatory response as it reduces the production of Th1 CD4-positive lymphocytes, favors the Th2 response through the induction of IL4, IL5, and IL10, and suppresses the Th17 response favoring the production of regulatory T cells [46]. As further evidence of its anti-inflammatory effects, vitamin D serum levels have been observed to correlate negatively with the neutrophil/lymphocyte ratio (NLR) [47]. This parameter is a well-known marker of inflammation that has been seen to be increased in CVD but also significantly increased in patients with ED [48], which negatively correlates with the severity of ED [49]. An RCT performed on a large cohort of adolescent girls showed that high-dose vitamin D supplementation (50,000 units weekly for 9 weeks) is able to reduce NLR values and, thus, systemic inflammation [50]. However, to our knowledge, no studies have also evaluated this in patients with ED. Despite the ample evidence in favor of the role of vitamin D on endothelial function, interventional studies evaluating the effects of supplementation on markers of endothelial function have yielded conflicting results and most often have failed to demonstrate any relationship [51]. Furthermore, meta-analytic studies that have collected evidence from interventional studies have also yielded conflicting results [52,53,54,55,56,57][52][53][54][55][56][57] and, in most cases, have not found an association between vitamin D supplementation and endothelial function [53,54,55,56][53][54][55][56] or found a correlation only in selected patients [57].

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