Low vitamin D doesn’t just weaken bones; it can sabotage sexual health, disrupt key biological defenses, and make common ED treatments less effective, according to new research.
Study: Vitamin D deficiency induces erectile dysfunction: Role of superoxide and Slpi. Image Credit: Lightspring / Shutterstock
In a recent study published in the British Journal of Pharmacology, researchers found that vitamin D deficiency induces erectile dysfunction (ED). ED is a highly prevalent condition, affecting 52% of males aged 40–70 in the United States (US) and 30% of European males aged 40–79. It adversely affects the quality of life and is recognized as a marker of poor health. Notably, ED is an independent predictor of future stroke and myocardial infarction. Further, metabolic diseases, diabetes, and obesity are known risk factors for sexual dysfunction.
Vitamin D has physiological functions beyond phosphorus and calcium homeostasis, such as regulating cell growth, immunity, and intracellular metabolism. Vitamin D deficiency is widespread, affecting over half the global population. The prevalence of vitamin D deficiency is higher in ED patients. Besides, ED severity is associated with plasma levels of 25-hydroxyvitamin D; however, the cause-and-effect relationship is unclear. While previous epidemiological studies have identified this association, the underlying mechanisms and direct causality, particularly in humans, have remained uncertain.
About the study
In the present study, researchers investigated whether isolated human corpora cavernosa (CC) from donors with vitamin D deficiency exhibit impairments in erectile function. Blood and cavernosal samples were obtained from 12 organ donors. It is important to note that while these ex vivo human tissue experiments are not influenced by hormonal or psychological factors, the sample size is relatively small, and the findings in humans are observational in nature. Further, a pilot study was performed in CC from Sprague-Dawley and Wistar rats fed a standard or vitamin D-free diet for five months.
Vitamin D receptor (Vdr) knockout mice were generated and used at four months of age. These mice were fed a γ-irradiated diet containing 20% lactose, 2% calcium, and 1.25% phosphorus to normalize mineral ion levels in the blood. Human CC strips were mounted and stretched to optimal isometric tension, and an initial response to 80 mM potassium chloride was recorded.
Further, neurogenic relaxations to electrical field stimulation (EFS) were obtained. Penile small helicine arterial rings were dissected and mounted on microvascular wire myographs for isometric tension recordings. Arteries were contracted with noradrenaline, and relaxation was measured by adding acetylcholine. Rat and mouse CC strips were placed in wire myographs and stretched.
Animal CC strips were incubated with atropine and guanethidine to inhibit muscarinic receptors and adrenergic neurotransmission and contracted with phenylephrine. EFS or vasoactive agents induced relaxations. Further, CC strips were transfected with specific small-interfering RNA (siRNA) against secretory leukocyte protease inhibitor (Slpi) and control non-targeting siRNA.
Mice and rats were anesthetized for intra-cavernosal pressure (ICP) measurement in the right cavernous nerve. Testosterone, SLPI, and 25-hydroxyvitamin D levels were measured using enzyme-linked immunosorbent assays in rat and human plasma. Further, total RNA was extracted for quantitative real-time polymerase chain reaction and sequencing.
Findings
Many donors had reduced responses to EFS in CC and moderately or severely reduced 25-hydroxyvitamin D levels. Notably, there were marked differences between participants with 25-hydroxyvitamin D levels below and above the cohort median value (35.5 nM). However, plasma testosterone levels were not correlated with 25-hydroxyvitamin D levels. Due to the small sample size, this lack of correlation with testosterone in humans should be interpreted with caution.
In rats fed a vitamin D-free diet, the reduction in 25-hydroxyvitamin D, without plasma calcium changes, significantly decreased EFS-induced relaxation. This vitamin D deficiency also significantly reduced acetylcholine-induced nitric oxide (NO)-dependent relaxation. Moreover, the relaxation induced by the phosphodiesterase 5 inhibitor (PDE5i) sildenafil (the first-choice drug for ED) was reduced.
However, the relaxation induced by riociguat, the soluble guanylyl cyclase stimulator, was unchanged. Besides, a vitamin D-free diet feeding significantly reduced 25-hydroxyvitamin D levels in plasma from Wistar rats. However, testosterone levels were unaffected. Notably, vitamin D deficiency markedly reduced the EFS-induced increase in ICP in anesthetized rats. CC strips isolated from vitamin D-deficient rats showed reduced EFS- and sildenafil-induced relaxation.
The study also found that vitamin D deficiency in rats led to increased penile fibrosis, as indicated by greater collagen deposition in penile tissue. Penile cavernous fibrosis is considered an important factor contributing to ED.
Further, the increase in ICP to EFS was lower in Vdr knockout mice than in wild-type mice, confirming ED. CC isolated from Vdr knockout mice showed reductions in EFS- and sildenafil-induced relaxations, but there were no changes in response to riociguat. Further experiments indicated that VDR ablation—and vitamin D deficiency-induced ED was mediated by increased superoxide production.
Transcriptomic analysis showed up- and down-regulation of several genes in vitamin D-deficient rats. Among these, Slpi was downregulated in CC from vitamin D-deficient rats. Notably, human donors with vitamin D deficiency also had reduced plasma SLPI. Finally, CC strips from healthy rats were incubated with SLPI or vehicle and exposed to pyrogallol (superoxide generator) with or without the superoxide scavenger, PEGylated superoxide dismutase (PEGSOD).
Because the relaxant responses to EFS were absent due to neural degeneration, only concentration-response curves to diethylamine NONOate (DEA-NO), an NO donor, were analyzed. Expectedly, pyrogallol diminished responses to DEA-NO due to the reaction of NO with superoxide. However, preincubation with SLPI alone did not modify the response to DEA-NO, but SLPI was able to partially reverse the reduction in relaxation caused by pyrogallol, indicating a protective effect against superoxide-induced ED.
Besides, PEGSOD prevented pyrogallol-induced ED. Slpi silencing in CC strips from healthy rats resulted in the downregulation of Slpi at levels comparable to those observed in vitamin D-deficient rats. Further, Slpi silencing significantly reduced the relaxant response to DEA-NO, implying that SLPI was necessary for erectile function. Notably, PEGSOD reverted the inhibitory effect of Slpi silencing.
Conclusions
In sum, the findings illustrate that vitamin D deficiency or ablation of the Vdr gene induces ED via increased superoxide and SLPI downregulation. Moreover, the results implicate vitamin D deficiency as an etiological factor for vascular ED and in the therapeutic failure of PDE5i. While these results suggest that improving vitamin D status in patients with ED and vitamin D deficiency could potentially enhance calcium metabolism, bone health, sexual performance, and ED treatment efficacy, the authors emphasize that further clinical studies are needed, and the direct applicability to humans requires additional research.