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Review

Does vitamin D deficiency contribute to erectile dysfunction?

Marc B. Sorenson Sunlight Institute; Saint George, UT USACorrespondence[email protected]
&
William B. Grant Sunlight, Nutrition, and Health Research Center; San Francisco, CA USA
Pages 128-136 | Received 12 Jan 2012, Accepted 11 Apr 2012, Published online: 01 Apr 2012

Abstract

Erectile dysfunction (ED) is a multifactorial disease, and its causes can be neurogenic, psychogenic, hormonal and vascular. ED is often an important indicator of cardiovascular disease (CVD) and a powerful early marker for asymptomatic CVD. Erection is a vascular event, and ED is often a vascular disease caused by endothelial damage and subsequent inhibition of vasodilation. We show here that risk factors associated with a higher CVD risk also associate with a higher ED risk. Such factors include diabetes mellitus, hypertension, arterial calcification and Inflammation in the vascular endothelium. Vitamin D deficiency is one of several dynamics that associates with increased CVD risk, but to our knowledge, it has not been studied as a possible contributor to ED. Here we examine research linking ED and CVD and discuss how vitamin D influences CVD and its classic risk factors—factors that also associate to increased ED risk. We also summarize research indicating that vitamin D associates with reduced risk of several nonvascular contributing factors for ED. We conclude that VDD contributes to ED. This hypothesis should be tested through observational and intervention studies.

Introduction: Important Facts Pertaining to this Discussion

Vitamin D is a steroid hormone produced in human skin by sunlight stimulation, specifically the ultraviolet-B (UVB) portion of the sunlight spectrum; about 80% of vitamin D is thus obtained.Citation1 The angle of sunlight varies greatly by season. In summer, the sun is overhead at noon, but in winter it stays closer to the horizon, and sunlight must pass through more atmosphere, which filters out much or all of the UVB. Therefore, availability of UVB exposure, and its resultant vitamin D production in skin, is highest in late spring through early fall and lowest from late fall through early spring. Consequently, vitamin D levels in the bloodstream also vary by season, with levels highest in late spring through early fall and lowest from late fall through early spring. For example, vitamin D levels in the UK are about 50% higher at the end of summer than at the end of winter.Citation1

Vitamin D deficiency (VDD) has increased profoundly in the last two decades. According to data from the National Health and Nutrition Examination Survey (NHANES), 45% of the US population had serum vitamin D levels of 30 ng/mL (considered adequate for healthCitation2) in 1998–1994, whereas in 2001–2004, this figure was only 23%, a drop of 49%.Citation3 Concomitantly, the incidence of erectile dysfunction (ED) is rising: worldwide, the number of men with ED will increase from 150 million in 1995 to an estimated 322 million in 2025.Citation4 ED is also prevalent in the US, affecting approximately 18–30 million men older than 20 y.Citation5,Citation6 Much of the worldwide upsurge may be due to an aging population, a deteriorating diet, lack of exercise and other unhealthful practices.

One recent study found risk of ED associated with “body mass index (BMI), irritative lower urinary tract symptoms, diabetes mellitus, chronic obstructive pulmonary disease (COPD) and sexual inactivity.”Citation7

“Most cases [of ED] have a multifactorial origin and it is admitted the influence on its pathogenesis of systemic diseases, different kind of drugs, psychogenic factors, cardiovascular, endocrinological and neurological diseases. Neurologic causes of erectile dysfunction may have their origins in the central or peripheral nervous system. Among possible process of neurogenic erectile dysfunction of central origin would be tumors, cerebral vascular accidents, encephalitis, Parkinson disease, multiple sclerosis and other demyelinization diseases, dementias, olivopontocerebellar degeneration and epilepsy.”Citation8

It has been estimated that about half of ED is related to vascular causes.Citation9 VDD also contributes to ED apart from its negative influence on classic CVD risk factors.

The Role of Vascular Disorders in ED

ED is an inability to produce an erection sufficiently rigid for sexual intercourse. ED incidence increases with age; the most severe form (defined as never being able to achieve an erection) occurs in 2% of men aged 20–39 y, increasing to 47% of men aged 75 y.Citation10

The penis is a highly vascularized organ, and erections are primarily vascular events.Citation11 Sexual stimulation causes the release of neurotransmitters from the corpus cavernosa (the two cylindrical chambers that run the length of the penis) and a relaxing factor, now established as nitric oxide (NO), from the endothelial cells of the penis.Citation12 NO is particularly important; vasodilation is essential to erection, and NO is the trigger for vasodilation in the vascular endothelium.Citation13,Citation14 The neurotransmitters, together with NO, cause the corpus cavernosa to relax and allow blood to flow into the penis, causing the penis to expand and sustain an erection until the process is reversed.Citation15 Any disorder causing endothelial dysfunction (END) will also interfere with vasodilation, which prevents erection. END is an early marker for the development of atherosclerosis.Citation16 In fact, END is the key factor in the pathophysiology of ED, and men with penile END also have END in other blood vessels.Citation17

The increase in the number of patients with CVD risk factors parallels the worldwide increase in ED prevalence,Citation18 which one would expect given that the two disorders result from intertwined disease processes.Citation19 Although nonvascular factors such as depression, fatigue, stress, Parkinson disease, multiple sclerosis (MS), and hypertensive medications may affect ED,Citation12 it is primarily a vasculogenic disease. Its most prevalent cause is the arterial occlusion of atherosclerosis, which also affects the coronary arteries and can lead to heart attackCitation11 or, in other parts of the body, vascular events such as strokeCitation20 and peripheral arterial disease (PAD).Citation21

Because the penile arteries are smaller than arteries supplying other areas of the body, the first symptoms of atherosclerosis may manifest as ED, making ED one of the best predictors of CVD.Citation13,Citation22–Citation25 Coronary artery disease is a CVD that is highly predictable by the presence of ED. Jackson and colleagues have stated that after the onset of ED, many men experience CVD symptoms in 2–3 y and then suffer cardiovascular events (such as heart attack or stroke) in 3–5 y.Citation26 One CVD, PAD, is also associated with the presence of ED. ED is an independent predictor of PAD, and increasing severity of ED is associated with increasing prevalence of PAD.Citation27

Bohm and colleagues, after conducting a 2 y, randomized, controlled trial to determine whether ED was a harbinger of CVD events, demonstrated that ED was a potent predictor of myocardial infarction, stroke, and heart failure in men with preexisting CVD. ED also predicted an increased hazard ratio of 1.84 (95% CI, 1.21–2.81; p = 0.005) for all-cause death.Citation28 In discussing the results of this study and the danger that ED drugs (phosphodiesterase-5 inhibitors) might pose by causing ED patients to ignore the presence of CVD, Bohm observed the following: “The drug works and the patient doesn’t show up anymore. These men are being treated for ED, but not the underlying cardiovascular disease. A whole segment of men is being placed at risk.”Citation29 Other researchers have concluded that the presence of ED should trigger an aggressive assessment for occult vascular disease.Citation11

Because both CVD and ED are, at least in part, vascular diseases, and ED is a potent predictor of CVD, the presence of risk factors for CVD also predicts the presence of ED,Citation30 and treatments that improve CVD often also do so for ED. Treatments with lifestyle changes, for example, are quite effective. Gupta and colleagues performed a meta-analysis of randomized, controlled clinical trials and demonstrated that with lifestyle modification and CVD risk-factor reduction programs in men with ED, sexual function increased by 2.4 times with lifestyle changes alone and by 2.66 times when statin therapy was included.Citation31 One effect of some statins is an increase in serum 25(OH)D concentrationsCitation32

One effective lifestyle change included a diet rich in whole grains, fruits, vegetables, legumes, walnuts, and olive oil; another was an exercise program (running or vigorous outdoor activity). Optimizing vitamin D levels through sunlight exposure or supplementation was not part of the lifestyle changes, but it should have been: VDD is associated with arterial stiffness and vascular dysfunction.Citation33,Citation34 Vasculogenic ED results from impaired smooth-muscle relaxation (endothelial-dependent or -independent), occlusion of the cavernosal arteries by atherosclerosis, or both.Citation17

The Role of Vitamin D and Sunlight on CVD

VDD is rampant among heart disease patients; University of Kansas researchers found that 70.3% of their heart disease patients had serum vitamin D levels below 30 ng/mL (the measure considered adequate for health) and that supplemental vitamin D was associated with a 61% reduction in the risk of death.Citation35 Giovannucci and colleagues showed that men with the lowest levels of serum vitamin D had a 2.4-times-increased risk of heart attack.Citation36

Possible Influence of Sunlight or Vitamin D on Four Major Risk Factors for CVD and ED

We hypothesize that optimizing vitamin D levels in men with ED could achieve similar positive influences on that disease. We first discuss four classic risk factors for CVD and ED and present research suggesting the influence of sunlight or vitamin D on each factor. We then briefly discuss other influences of vitamin D on ED that have not been thoroughly covered in conjunction with the four common risk factors discussed.

Arterial calcification

Arterial calcification is a common feature of atherosclerosis, occurring in more than 90% of angiographically significant lesions.Citation37 Measures of arterial calcification have been used since 1964 to predict myocardial infarct,Citation38 and in 1990, 83–90% of CVD patients showed calcification of their coronary arteries—a far higher percentage than disease-free people.Citation39 Arterial calcification remains a strong marker of increased risk of CVD,Citation40,Citation41 independent of other known risk factors.Citation42,Citation43

Arterial calcification is also a risk factor for ED. Lee and colleagues demonstrated that men who had ED were about 40% more likely to have measurable coronary artery calcification than those without ED.Citation44 They concluded that ED “is significantly associated with abnormal coronary artery calcification and, like PAD, might warrant consideration as a coronary artery disease risk equivalent.”

Serum vitamin D levels and arterial calcification have a strong inverse relationship,Citation37 provided that vitamin D levels are not excessively high, which can exacerbate calcification. Zittermann and colleagues explain that vitamin D exerts a biphasic dose–response curve on vascular calcification with deleterious consequences not only for vitamin D excess but also for VDD. They also note, however, that vitamin D excess seldom occurs in the general population.Citation45 These researchers also mention that in rats, low levels of activated vitamin D (1,25-dihydroxyvitamin D or calcitriol) are associated with massive calcification of blood vessels and other soft tissues.

We hypothesize that optimizing vitamin D levels through sunlight exposure or supplementation would have positive benefits for those suffering from ED associated with vascular calcification.

Diabetes mellitus

Diabetes mellitus (DM) is a disorder of carbohydrate metabolism characterized by excessive glucose levels in urine due either to inadequate production of insulin (insulin-dependent, or type-1 DM) or to poor insulin utilization (adult-onset, or type-2 DM), both of which result in increased urine flow. Ninety percent to 95% of diabetes cases in the US are type-2.Citation46 The presence of DM is a profound predictor of CVD, correlating to an increased risk of CVD of approximately 2.5 times.Citation47 Although incidence of CVD has decreased somewhat in the past few decades, it has done so only in those without DM. The incidence of DM rapidly increased from 1970 to 2000,Citation48 especially during the 1990s, and those with DM have shown a dramatic upsurge in the risk of CVD. For example, during the 1990s, the risk of acute myocardial infarction increased among those with DM by 51%, and general CVD rates in men with DM increased by 61%.Citation49 Diabetes leads to CVD by causing END, a precursor to atherosclerosis, as follows:Citation50 High levels of glucose in the blood inhibit the production of NO.Citation51 This inhibition impairs vasodilation of vessels and leads to atherosclerosisCitation52 by promoting vasoconstriction, hypertension, vascular smooth-muscle growth, inflammation, expression of cellular adhesion molecules (CAMs), platelet activation, decreased fibrinolysis and thrombosis.Citation53 Both type-1 and type-2 DM follow this pattern. Awad and colleagues stated that “the diabetes control and complications trial clearly showed that better long-term control of blood glucose in diabetes type-1 is associated with decreased frequency and delayed the onset of microvascular complications.”Citation54 These changes in the vessel walls affect the brain as well as the heart: diabetics younger than 55 y have 11.6 times the risk of stroke.Citation55

DM also is associated closely with the risk of ED, as one would expect given how DM damages the vascular system. Reviewing the literature, Phe and Roupret concluded that “the pathophysiology is multifactorial, involving END, specific complications of diabetes and psychological factors.”Citation56 In fact, compared with nondiabetic men, men with DM have three to four times the risk of ED,Citation57,Citation58 and the likelihood of ED in diabetic men ranges from 35–90%.Citation59 ED in men with diabetes also occurs 10–15 y earlier.Citation60

Sunlight exposure relates to DM. One paper showed that blood sugar levels are lower during summer than in winter,Citation61 and another showed that exposure to UVB light increases insulin secretion.Citation62

Vitamin D research indicates a close association between vitamin D and DM. Pittas and colleagues reported on research conducted on adults with impaired sugar tolerance and insulin resistance (both risk factors for diabetes). For 3 y, half received a placebo and the other half received vitamin D plus calcium. The rise in blood sugar levels was 15 times higher in the placebo group, and their increase in insulin resistance was 18 times higher.Citation63 Moreover, a 4-week program of high-dose vitamin D supplementation (10,000 IU daily) in subjects with impaired fasting glucose was associated with an improved insulin sensitivity and a decreased acute insulin response to glucose, both risk factors for DM.Citation64 Finally, a 16-week randomized, placebo-controlled study demonstrated that subjects who took 2,000 IU of vitamin D3 daily had increased β-cell function, as shown by a 37% improvement in insulin secretion.Citation65

We hypothesize that vitamin D optimization through sunlight exposure and/or vitamin D3 supplementation would decrease END and subsequent vascular damage caused by diabetes and would reduce the risk of ED.

Hypertension and stroke

High blood pressure, or hypertension, especially systolic pressure, is a vascular disorder that is a potent predictor of CVD,Citation66 and a strong, linear, and independent relationship exists between the two.Citation67 Hypertension is also one of the most important risk factors for stroke.Citation68,Citation69 Hypertension leads to END, which is mediated by impaired NO availability after oxidative stress.Citation16

Hypertension is also a risk factor for ED,Citation70 which afflicts to some degree 68% of men with hypertension.Citation71,Citation72 Because hypertension leads to vascular damage and END, one would expect this outcome. The hypertension–ED–stroke connection is clear in the fact that over a 5-y period, men with ED have a 29% higher risk of stroke than those without ED.Citation73

The control of renin and angiotensin also affects hypertension. Renin is an enzyme that profoundly raises blood pressure by activating the peptide angiotensin, a vasoconstrictor.Citation74 Vitamin D may suppress hypertension by modulating the renin-angiotensin system,Citation75,Citation76 a regulatory cascade essential in regulating blood pressure.Citation77 Vitamin D is a potent endocrine suppressor of renin biosynthesis, and VDD stimulates renin expression in normal mice.Citation75 Also, mice lacking vitamin D receptors produce more renin and angiotensin, leading to hypertension.Citation77

A direct relationship exists among hypertension, sunlight exposure, and stroke; the incidence of hypertension is considerably higher in winter than summer. One study of elderly hypertensive subjects showed that blood pressure levels averaged 165/90 in winter but 134/74 in the summer, and both stroke and heart attack rates doubled in winter.Citation78 Hypertension also follows the same pattern in children.Citation79 UVB light from sun lamps also effectively treats hypertension. In subjects who participated in three sessions per week of whole-body UVB exposure, vitamin D levels rose 162% after 6 weeks, and blood pressure dropped six points on both systolic and diastolic measurements.Citation80

Sunlight exposure’s ability to lower blood pressure may also be due to another spectrum of UV light—UVA. Opländer and colleagues demonstrated that whole-body irradiation with UVA lowered systemic blood pressure by stimulating NO production, significantly increasing intradermal levels of NO. These increased NO levels were accompanied by increased flow-mediated vasodilation of the brachial artery.Citation81 Such vasodilation could also enhance sexual function in men by lessening ED. Another investigation showed that men with the lowest vitamin D levels also had 6.13 times the risk of developing hypertension; women with the lowest levels had 2.67 times the risk.Citation82 Other investigations show a close association between VDD and the likelihood of stroke.Citation83

We hypothesize that vitamin D optimization through sunlight exposure or vitamin D3 supplementation would decrease vascular damage caused by hypertension and reduce the risk of ED.

Inflammation in the vascular endothelium

Inflammation is a reaction of damaged tissue that manifests as redness, swelling, pain, tenderness and heat. It is primarily a protective response against injury. Normal vascular endothelium has anti-inflammatory properties, but endothelial function is impaired in the presence of inflammatory conditions and increased oxidative stress.Citation17,Citation84 When injurious agents persist or healing is disturbed, inflammation, tissue injury and attempts at repair coexist. This combination of factors can lead to chronic inflammation, harming many body systems, including the vascular system.Citation85 Inflammation drives the formation, progression, and rupture of atherosclerotic plaques; it is one of the stimuli that cause CAMs to further recruit inflammatory blood monocytes that adhere to the endothelium, and through chemotactic stimulus by inflammatory proteins known as chemokines and inflammatory cytokines, enter between the endothelial cells and invade the intima of the blood vessel. In the intima, they mature into macrophages, which engulf lipids and create foam cells, leading to atherosclerotic lesions.Citation86,Citation87 Macrophages also release growth factors that are destructive to blood vessels.Citation88-Citation91, Even subclinical inflammation affects endothelial function and is involved in all stages of atherosclerosis.Citation17 Thus, the endothelium as well as the entire blood vessel is damaged, and atherosclerosis proceeds.

ED is also closely associated with inflammation. C-reactive protein (CRP), a major marker of inflammation, is significantly higher in patients with ED than in subjects without ED.Citation92,Citation93 Interestingly, CRP itself reduces production of NO, leading to further vascular damage.Citation94 Also, CAMs are increased in men with ED who have not manifested cardiovascular risk factors or overt vascular damage.Citation95 Another marker of inflammation is tumor necrosis factor α (TNFα), an inflammatory cytokine that is markedly elevated in men with ED and is another common link between ED and CVD.Citation96

Vitamin D may promote vascular health by inhibiting inflammation.Citation97 Vitamin D supplements and injections may lower CRP levels as much as 40%Citation98 and improve cytokine profiles; it inhibits the production of proinflammatory cytokinesCitation99,Citation100 while stimulating the production of anti-inflammatory cytokines.Citation100,Citation101 One pro-inflammatory cytokine, TNFα, is inversely related to regular exposure to sunlight and artificial sources of UVB among women,Citation102 and the same is probably true for men. Two CAMs induced by TNFα are also significantly decreased after incubation with activated vitamin D.Citation103 In addition, Oh and colleagues have shown that in patients with type 2 diabetes, active vitamin D inhibits foam cell formation and suppresses macrophage cholesterol uptake,Citation104,Citation105 inhibiting the inflammatory atherosclerotic process described earlier.

We hypothesize that vitamin D optimization through sunlight exposure or vitamin D3 supplementation would decrease vascular damage caused by inflammation and reduce the risk of ED. We searched pubmed.gov for evidence contradicting our hypothesis regarding VDD and ED but found none.

Other influences of vitamin D on ED

Endothelial-progenitor cells

Endothelial progenitor cells (EPCs) are necessary for maintaining the health of the arterial endothelium. VDD is associated with depletion of EPCs and consequent END in patients with type 2 DM.Citation106 This research also showed that VDD was associated with reduced vasodilation as measured by brachial artery flow–mediated dilation.

NO synthases

NO synthases (NOS) are a family of enzymes that catalyze the production of NO from l-arginine. Activated vitamin D stimulates the production of substantial quantities of NOS and NO in macrophages produced in response to tuberculosis,Citation107 in boneCitation108 and in endothelial cells,Citation109 the last being vital to vascular dilation and thereby important to inhibiting ED. This behavior may explain why endothelium-derived, NO-evoked dilation is halved in arteries from vitamin D–deficient male rats.Citation110

PAD

PAD is a CVD that is closely associated with the presence of ED. Chua and colleagues have shown that VDD could be an easily correctable independent risk factor for PAD.Citation111

Platelet activation

Platelet activation by proinflammatory factors is another aspect of END. In experiments, vitamin D attenuates platelet activation while reducing the expression of two CAMs, VCAM-1 and MT1-MMP.Citation112 Researchers in Israel also identified 50 patients who had a heart attack or an episode of unstable angina, placing half of them on a regimen of 4,000 IU of vitamin D daily for 5 d. The vitamin D group showed a decrease in VCAM-1 as well as another inflammation marker, interleukin 6. The patients who did not receive vitamin D showed clear increases in both inflammation markers.Citation113 The researchers stated, “VCAM-1 is central to atherosclerotic plaque formation and [interleukin 6] is broadly associated with coronary risk.” Both studies indicate that vitamin D has actions that reduce END and thereby have a positive influence on ED.

Vascular smooth-muscle cell proliferation

Vascular smooth-muscle cell (VSMC) proliferation is part of the process of atherosclerosis. Vitamin D has an antiproliferative influence on VSMC,Citation114,Citation115 which indicates antiatherosclerotic properties that may positively influence ED.

Vasodilation

Vasodilation is vital to achieving erection. VDD is inversely associated with flow-mediated vasodilation, END, and arterial stiffness irrespective of the traditional risk factors for CVD and EDCitation33 discussed here. Therefore, VDD—in addition to exacerbating the classical risk factors for CVD—may directly lead to ED.

Nonvascular conditions comorbid with ED and influenced by vitamin D

We have thus far discussed the relationship of ED to CVD and considered the influence of vitamin D levels or treatment on both disorders. Evidence in addition to that presented in this review in support of the hypothesis that VDD contributes to ED risk was sought by searching pubmed.gov for papers linking ED to sun exposure, race, and disorders linked to VDD, and whether animal models regarding vitamin D and ED had been conducted. No evidence linking ED to sun exposure was found. No animal model studies of ED and vitamin D were found. In a cross-sectional study in the United States in 2000 and 2001, the estimated prevalence of ED was “21.9% (95% CI, 18.8–24.9) in whites, 24.4% (95% CI, 18.4–30.5) in blacks, and 19.9% (95% CI, 13.9–25.9) in Hispanics.”Citation116 Another paper reported that Black and Hispanic men in the Boston area had 25% higher rate of ED, but attributed the finding to socioeconomic status rather than raceCitation117

Several other nonvascular diseases and conditions are closely associated with both ED and VDD, strengthening the hypothesis that VDD contributes to ED and offering another avenue whereby vitamin D optimization might mitigate or reverse it. Those diseases and conditions include Alzheimer,Citation118,Citation119 asthma,Citation120,Citation121 chronic kidney disease,Citation122-Citation124 depression,Citation125,Citation126 falls and fractures,Citation127,Citation128 metabolic syndrome,Citation129,Citation130 MS,Citation131-Citation134 obesity,Citation135,Citation136 Parkinson,Citation137,Citation138 periodontal disease,Citation139,Citation140 psoriasisCitation141,Citation142 and smoking.Citation143,Citation144 summarizes research regarding those diseases and conditions. For all of these diseases, VDD appears to be an important risk factor. Thus, avoiding VDD earlier in life may reduce the risk of ED. In addition, for some of the diseases such as atopic dermatitisCitation145,Citation146 and multiple sclerosis, increasing vitamin D intake or production can reduce the symptoms and may also reduce the risk of ED.

Table 1. Evidence for influences of vitamin D on nonvascular diseases and conditions associated with ED

Conclusion

The research presented suggests that many common mechanisms underlie both CVD and ED, and that VDD is closely associated with both disorders. We hypothesize that optimizing serum vitamin D levels through sunlight exposure or vitamin D supplementation helps delay the onset of ED. Coupled with positive changes in lifestyle, such optimization may restore normal sexual function to some men. This hypothesis should be tested through observational and intervention studies. If proven by further research, such therapy would offer an alternative or complement to phosphodiesterase-5 inhibitors, which, though exceptionally effective and a first choice for treatment, have been associated with many negative side effects,Citation147 and which, because of their efficacy in producing erections, may cause men with ED to ignore the possibility they might have occult underlying CVD.

Abbreviations:
CAM=

cellular adhesion molecules

95% CI=

95% confidence interval

CRP=

C-reactive protein

CVD=

cardiovascular disease

DM=

diabetes mellitus

ED=

erectile dysfunction

END=

endothelial dysfunction

NO=

nitric oxide

NOS=

nitric oxide synthases

PAD=

peripheral arterial disease

UVB=

ultraviolet-B

VDD=

vitamin D deficiency

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