Abstract
Objective: The objective of this study is to investigate the impact of metabolic status on associations of serum vitamin D with hypogonadism and lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH).
Patients and methods: A total of 612 men underwent physical examination, biochemical/hormonal blood testing, and transrectal prostate ultrasound. Moreover, the subjects filled out standard questionnaires for identification and grading of LUTS and hypogonadism symptoms. Parameters were statistically compared with independent t-tests and correlation analyses.
Results: Vitamin D levels positively correlated with total testosterone (TT) but not with prostate volume or International Prostate Symptom Score (IPSS). Patients with metabolic syndrome had significantly lower vitamin D levels, which were not correlated with TT, prostate volume, or IPSS. However, vitamin D was positively correlated with TT, and negatively correlated with prostate volume and quality-of-life IPSS in subjects without metabolic syndrome.
Conclusion: The clinical usefulness of vitamin D for treatment of hypogonadism or LUTS/BPH varies according to metabolic status.
Introduction
Several studies have demonstrated a relationship between the serum vitamin D and total testosterone (TT) levels [Citation1,Citation2]. Vitamin D deficiency is known to be associated with frailty [Citation3], cardiovascular disease [Citation4], inflammatory disease [Citation5], and higher all-cause mortality [Citation6]. The serum testosterone level declines with age, and has also been reported as a risk factor for cardiovascular disease as well as cancer and all-cause mortality [Citation7]. Thus, it is important to consider the relationships of vitamin D with testosterone and hypogonadism. Tak et al. [Citation1] reported a statistically significant positive correlation between testosterone and serum 25 (OH)D in Korean men. Wang et al. [Citation2] performed a cross-sectional study of 2854 Chinese men, and also found a positive correlation for serum vitamin D level with serum TT and estradiol levels. Conversely, Lee et al. [Citation8] performed a cross-sectional study in 3369 relatively healthy men, and after correcting for various confounding factors found no significant correlation between the 25 (OH)D level and serum testosterone level. Several studies have attempted to find associations between lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH) and serum vitamin D levels; although such relationships were clearly detected, no statistically significant association was detected between serum testosterone and vitamin D [Citation9,Citation10]. Furthermore, although many studies have shown an association of vitamin D with BPH, studies on the relationship between vitamin D and testosterone have shown inconsistent results.
A possible reason for these discrepant results could be that both vitamin D and testosterone are associated with metabolic syndrome [Citation11,Citation12]; thus, ignoring the metabolic component might mask the relationship between serum vitamin D and testosterone. Since the prostate is also influenced by metabolic factors, metabolic status can also be considered to affect the relationship between LUTS/BPH and vitamin D [Citation13–16]. Therefore, in the present study, we aimed to investigate the impact of components of metabolic syndrome on the relationships of serum vitamin D with testosterone and with LUTS/BPH.
Patients and methods
The subjects included in this study consisted of 612 men who visited the Health Examination Center at our hospital for a regular health checkup in March–June or September–November 2015 (excluding July–August and December–February, which have the highest and lowest levels of solar radiation, respectively). The patients underwent an interview for medical history, blood pressure measurements, and physical examination (body mass index and waist circumference). Biochemical/hormonal blood testing (fasting glucose, total cholesterol, high-density lipoprotein [HDL], and low-density lipoprotein [LDL] cholesterol, triglycerides [TG], TT, vitamin D, calcium, phosphate, homocysteine) was performed before 11 a.m. The subjects also completed the International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF), and Aging Male Symptom scale (AMS) tests, which enable identification and grading of hypogonadism and LUTS. Finally, transrectal ultrasound prostate evaluations were performed on 200 of the subjects. Metabolic syndrome was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III criteria. Specifically, metabolic syndrome was diagnosed in subjects who satisfied at least three of the following criteria: waist circumference >40 in, fasting glucose >100 mg/dL or pharmacologic treatment (Rx), TG >150 mg/dL, HDL <40 mg/dL or Rx, hypertension >130 systolic or >85 mmHg diastolic or Rx. Statistical evaluation was performed using independent t-tests and simple correlation analyses, with statistical significance defined as p < .05.
Results
The mean age of the men who participated in the study was 48.3 ± 7.8 years, and 135 of the subjects were diagnosed with metabolic syndrome according to the NCEP ATP III criteria. Simple correlation analysis showed that the serum vitamin D level was positively correlated with the serum TT level and HDL (r = .161, p < .001; r = .093, p = .021, respectively), while TG, homocysteine, and the number of metabolic components showed significant negative correlations with vitamin D levels (r = –.235, p < .001; r = –.169, p = .003; r = –.178, p < .001, respectively). Vitamin D was negatively correlated with prostate volume and the quality-of life (QoL) IPSS, and was positively correlated with total IPSS, although these relationships were not statistically significant (r = –.129, p = .086; r = –.119, p = .119; r = .116, p = .129, respectively).
We used the NCEP ATP III metabolic syndrome criteria to divide participants into a metabolic syndrome group and a no metabolic syndrome group for comparison between the groups. The level of vitamin D was significantly lower in the group diagnosed with metabolic syndrome than in the group without a diagnosis of metabolic syndrome (p = .001). In addition, the serum testosterone level was also significantly lower in the metabolic syndrome group than in the no metabolic syndrome group (p = .004). The prevalence of testosterone deficiency (TD) also showed a significant difference between groups, with a rate of 14.68% and 26.67% in the group without and with metabolic syndrome, respectively (p = .001). Moreover, total scores and psycho-component scores of the AMS, which reflect the severity of TD symptoms, indicated significantly better symptoms in the group without metabolic syndrome compared with the group with metabolic syndrome (p = .028 and p = .007, respectively; ).
Table 1. Parameters and characteristics of study participants according to the presence (+) or absence (–) of metabolic syndrome (MS).
We further analyzed the association between serum vitamin D level and the other variables according to a diagnosis of metabolic syndrome. In a simple correlation analysis for the 135 subjects diagnosed with metabolic syndrome, TG was the only variable that showed a significant correlation with the vitamin D level (). Conversely, when we analyzed the 477 subjects without metabolic syndrome, the testosterone level, total IIEF score, and orgasmic function all showed significant positive correlations, while TG, homocysteine, prostate volume, and IPSS QoL scores showed significant negative correlations with vitamin D levels ().
Table 2. Correlation analysis of vitamin D levels with measured parameters for the subjects diagnosed with metabolic syndrome.
Table 3. Correlation analysis of vitamin D level with measured parameters in subjects without a diagnosis of metabolic syndrome.
Discussion
Vitamin D has previously been shown to affect prostate size and LUTS in various cross-sectional and molecular studies [Citation17]. By binding to vitamin D receptor (VDR), vitamin D increases prostate cell differentiation, decreases cell proliferation, and increases apoptosis [Citation18]. Furthermore, vitamin D has pronounced immunoregulatory and anti-inflammatory properties [Citation19], and seems to act by regulating the growth of stromal cells of the prostate. Ruan et al. [Citation20] demonstrated that a single nucleotide polymorphism in the VDR gene is associated with BPH progression, and Yalçınkaya et al. [Citation21] reported associations among the renin-angiotensin system, vitamin D, and BPH pathogenesis. In a double-blinded randomized controlled study, Colli et al. [Citation22] went beyond simply showing a correlation, and reported that prostate size was reduced by 2.9% when BPH patients with a prostate volume of at least 40 mL took 6000 IU of a vitamin D analog every day for 10 months. In the same study, 28.9% of the patients responded to vitamin D supplementation, while only 7.7% showed no response [Citation22]. This demonstrates the potential benefits of using vitamin D supplementation in clinical practice. However, unlike BPH, studies exploring the association of serum vitamin D with serum testosterone and hypogonadism have shown inconsistent results. Although some studies have shown a significant positive correlation between the serum vitamin D and testosterone levels [Citation1,Citation2], other studies failed to demonstrate statistically significant results [Citation8–10]. Recently, Canguven et al. [Citation23] showed that vitamin D treatment improves testosterone levels and metabolic syndrome in middle-aged men, but it was not a randomized placebo-controlled trial and baseline TT level of the patients enrolled in this study was within normal TT range.
Both animal model and human studies have demonstrated that vitamin D is essential for optimal male reproductive function [Citation1]. The effects of vitamin D are presumably mediated by the existence of VDR and vitamin D-metabolizing enzymes in the adult male reproductive tract, male germ cells, and Leydig cells, which are the main sites of testosterone synthesis in males [Citation24,Citation25]. Moreover, given that reduced serum vitamin D and testosterone levels both increase the risk of cardiovascular disease [Citation4] and all-cause mortality [Citation6,Citation7], if it were possible to demonstrate a clear association between hypogonadism and serum vitamin D, as well as the benefits of vitamin D supplementation in the treatment of hypogonadism (as in the case of BPH), the effectiveness of testosterone treatment in patients with hypogonadism could be improved, which would further help to reduce the treatment duration, thereby lowering the risks associated with testosterone treatment. An important consideration of such evaluations is the close relationship of both serum vitamin D and testosterone with metabolic syndrome [Citation11,Citation12], which has been largely ignored in previous studies. Therefore, we conducted the present study based on the assumption that the inconsistent results on the relationship between serum vitamin D and serum testosterone could be explained by the unmeasured effects of metabolic components.
In line with this prediction, the results of our study showed that subjects diagnosed with metabolic syndrome showed significantly lower serum vitamin D and testosterone levels than those without metabolic syndrome, and also had significantly higher hypogonadism prevalence and hypogonadism symptom scores. In a separate analysis of only the subjects diagnosed with metabolic syndrome, we found no significant correlations for serum vitamin D with testosterone, TD symptom scores, prostate volume, or LUTS. Conversely, in the group without metabolic syndrome, serum vitamin D level showed a significant positive correlation with serum testosterone level, as well as with erectile symptoms, which are both related to hypogonadism. Moreover, the serum vitamin D level showed significant negative correlations with prostate volume and the QoL IPSS in this group. Thus, we demonstrated that the correlations of serum vitamin D level with hypogonadism and with LUTS/BPH differ according to metabolic status. Our results are consistent with the findings of Glueck et al. [Citation26], who reported a significant negative correlation between serum vitamin D and homocysteine levels. Thus, further research into the mechanisms driving these links between serum vitamin D, testosterone, and homocysteine will be required.
One of the key strengths of this study is that we did not recruit subjects in July–August and November–February in order to minimize the difference in vitamin D levels due to solar radiation. In addition, we analyzed the correlation of vitamin D level with LUTS/BPH as well as with hypogonadism. However, our study also has the following limitations. First, because this was a cross-sectional study in which serum TT and vitamin D levels were only measured once, we were unable to investigate changes in the relationships between variables according to season, and could not measure parathyroid hormone levels, which play an important role in regulating serum vitamin D levels. Longitudinal studies with systematic sampling of subjects including parathyroid hormone measurements throughout the year are warranted to better elucidate these effects. In addition, the subjects were relatively young and we only examined Korean men, making it difficult to directly compare and apply our results generally to other ethnicities, or to all age groups. Furthermore, prostate size was only measured in 200 participants, which is a relatively low number compared with other studies, which may have limited the statistical significance of our results. Indeed, in the analysis of all participants, we did not find a significant association of serum vitamin D with prostate volume or LUTS, even though such correlations have been shown in many previous studies, which we believe is largely due to the small number of participants. Nevertheless, we demonstrated that metabolic components clearly affect the relationship between vitamin D and testosterone levels, which has been inconsistent in previous studies. Moreover, we provide the first demonstration that metabolic components should be considered when determining the relationship between the serum vitamin D level and LUTS/BPH.
Conclusions
The association of serum vitamin D with hypogonadism and LUTS/BPH varied according to the presence or absence of metabolic syndrome. Therefore, in treating patients with hypogonadism or LUTS/BPH, the clinical usefulness of vitamin D might differ depending on the patient's metabolic status.
Disclosure statement
The authors declare that there are no financial disclosures or conflicts of interest regarding this manuscript.
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