In the last decade, vitamin D has emerged as a pleiotropic molecule with a multitude of autocrine, paracrine and endocrine functions, mediated by classical genomic as well as non-classical non-genomic actions, on multiple target organs and systems. The expression of vitamin D receptor and vitamin D metabolizing enzymes in male reproductive system, particularly in the testis, suggests the occurrence of vitamin D synthesis and regulation as well as function in the testis. The role of vitamin D in the modulation of testis functions, including hormone production and spermatogenesis, has been investigated in animals and humans. Experimental studies support a beneficial effect of vitamin D on male fertility, by modulating hormone production through genomic and non-genomic actions, and, particularly, by improving semen quality essentially through non-genomic actions. However, clinical studies in humans are controversial. Indeed, vitamin D seems to contribute to the modulation of the bioavailable rather than total testosterone. Moreover, although an increased prevalence or risk for testosterone deficiency was reported in men with vitamin D deficiency in observational studies, the majority of interventional studies demonstrated the lack of effect of vitamin D supplementation on circulating levels of testosterone. The most consistent effect of vitamin D was reported on semen quality. Indeed, vitamin D was shown to be positively associated to sperm motility, and to exert direct actions on spermatozoa, including non-genomic driven modulation of intracellular calcium homeostasis and activation of molecular pathways involved in sperm motility, capacitation and acrosome reaction. The current review provides a summary of current knowledge on the role of vitamin D in male fertility, by reporting clinical and experimental studies in humans and animals addressing the relationship between vitamin D and testis function.

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The role of vitamin D in male fertility: A focus on the testis

Vitamin D deficiency is a common health issue around the world. We therefore evaluated the associations of semen quality with both serum and seminal plasma vitamin D levels and studied the mechanisms underlying these by incubating spermatozoa with 1,25(OH)2D In vitro. Two hundred and twenty-two men were included in our study. Vitamin D was detected using an electrochemiluminescence method. Spermatozoa used for In vitro experiments were isolated by density gradient centrifugation. Positive relationships of serum 25(OH)D with semen volume and seminal plasma fructose were identified. Seminal plasma 25(OH)D level showed no relationship with serum 25(OH)D level, while it was inversely associated with sperm concentration and positively correlated with semen volume and sperm kinetic values. In vitro, sperm kinetic parameters increased after incubation with 1,25(OH)2D, especially upon incubation for 30 min with it at a concentration of 0.1 nmol l-1. Under these incubation conditions, the upward migration of spermatozoa increased remarkably with increasing adenosine triphosphate (ATP) concentration. The concentration of cyclic adenosine monophosphate (cAMP) and the activity of protein kinase A (PKA) were both elevated, and the PKA inhibitor, N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H89) reversed the increase of ATP production. The concentrations of cytoplasmic calcium ions and nicotinamide adenine dinucleotide (NADH) were both enhanced, while mitochondrial calcium uniporter (MCU) inhibitor, Ruthenium 360 (Ru360) did not reverse the increase of ATP production. Therefore, seminal plasma vitamin D may be involved in regulating sperm motility, and 1,25(OH)2D may enhance sperm motility by promoting the synthesis of ATP both through the cAMP/PKA pathway and the increase in intracellular calcium ions.

The effect of vitamin D on sperm motility and the underlying mechanism.

A number of studies have examined the association between dietary patterns and semen quality, but the findings have been inconclusive. Herein, we conducted a systematic review and meta-analysis of observational studies to assess the association between dietary patterns and semen quality. PubMed, Cochrane library, Science direct, Scopus, Google Scholar, and ISI web of science databases were searched up to August 2016 for observational studies assessing the association between common dietary patterns and sperm quality markers. Data were pooled by the generic inverse variance method with random effects and expressed as mean differences with 95% confidence intervals (CIs). Heterogeneity was assessed (Cochrane Q-statistic) and quantified (I2 -statistic). The Newcastle-Ottawa Scale assessed study quality. Six eligible studies, involving 8207 participants, were included in our systematic review and meta-analysis. The pooled mean difference of sperm concentration for the healthy dietary pattern versus unhealthy dietary pattern intake was mean difference: 0.66; 95% CI, 0.305-1.016; p < 0.001. In comparison with those who had the highest adherence to healthy dietary pattern, individuals in the lowest adherence had significantly lower level of sperm concentration. However, no significant association was seen between eating patterns and other semen quality. Healthy dietary pattern seems to be associated with elevated sperm concentration level. Further longitudinal studies are needed to clarify this relationship.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/andr.12430

Dietary patterns and semen quality: a systematic review and meta-analysis of observational studies

To date, the key role of vitamin D in male reproductive system has been suggested, since the expression of vitamin D receptors and metabolizing enzymes was demonstrated in the testis and spermatozoa. Nevertheless, a general consensus about the role of vitamin D in male fertility is still debated. The aim of this review is to provide an updated systematic revision of the current available literature, discussing the experimental and clinical evidence on the role of vitamin D in the regulation of testis hormone production, seminal parameters and male fertility. The consequences of vitamin D deficiency on serum levels of testicular hormones have been analysed by several observational and interventional studies, with controversial results. Equally, the experimental researches not were able to state a certain relationship between vitamin D status and testis hormone production. Possible bias, including age, body mass index, and baseline vitamin D status justified the differences among studies. As well as concerning the effect of vitamin D on semen parameters, most of the studies agreed in the possibility that vitamin D might have a positive effect on human male fertility potential, particularly through better sperm motility. Regarding pregnancy outcomes, normal level of vitamin D seems to be related to better pregnancies. However, all the previous studies displayed a wide heterogeneity in study design, population, methodology, and cut off values used for the evaluation of vitamin D status. Future studies are needed to better clarify the exact role of vitamin D on hormonal and seminal panel in both fertile and infertile men.

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Vitamin D and Male Fertility: An Updated Review.

Background: The prevalence of infertility and vitamin D deficiency is common in Pakistan. Therefore, our study aims were to assess and compare Vitamin D; 25-hydroxyvitamin (25OHD) and reproductive hormone levels in male fertile and infertile subjects with normal and abnormal sperm parameters. Furthermore, the study is aimed to explore the association of 25OHD levels with these sperm parameters in a selected population of Karachi, Pakistan. Methods: The cross-sectional study was carried out from August 2016 till December 2017, 313 study subjects were recruited from an Infertile Clinic from Islamabad, Pakistan, and the general population. First, we took the couples’ history of parenting and then carried out a semen analysis and infertile and fertile male subjects were then subgrouped into ‘normal’ and ‘altered sperm parameter/s.’ Forward linear regression was done for selection of 25OHD as a significant predictor of sperm parameters. Results: The median values of the total count, motility, morphology as well as serum 25OHD were significantly higher in the group with ‘normal’ (186) as compared to subjects (127) in ‘abnormal sperm parameters’ group. The 25OHD levels were significantly high in males with ‘normal sperm parameters’; 80.90 ± 23.33 nmol/L vs. “altered sperm parameter/s’, 64.68 ± 24.21 nmol/L (mean ± SD) with p < 0.001. Serum testosterone level had a significant positive correlation with 25OHD while LH had a significant negative correlation with 25OHD (p<.001), and FSH level had a non-significant negative correlation with 25OHD. Results of regression model showed one unit increase of motility would give 0.15-unit positive significant impact on 25OHD; 20% variation in 25OHD was explained by the total count, motility, and morphology, while the model was adjusted for BMI. Conclusion: The impact of 25OHD levels on sperm parameters can be emphasized on the basis of detection of its high serum levels in ‘normal’ subjects in both fertile as well as infertile males in comparison to subjects that had altered sperm parameters; total sperm count, motility, and normal morphology. The considerably positive association between 25OHD, testosterone, total count, motility, and morphology further accentuates its impact on normal spermatogenesis and the male reproductive functions required for acquiring fertility.

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Association Between Vitamin D, Reproductive Hormones and Sperm Parameters in Infertile Male Subjects.

Summary
Although vitamin D deficiency is one of the most common health problems throughout the world, including Iran, conflicting information exists on the potential association between serum vitamin D levels and semen quality This study intended to evaluate the association between serum vitamin D [25(OH) D3] with semen quality and hormones in Iranian subfertile men We also compared mean vitamin D and hormone levels in normospermic men with oligoasthenoteratozoospermia (OAT) men This cross-sectional study was conducted on 278 men who were referred to Royan Infertility Clinic (Tehran, Iran) from March to September 2014 The participants were categorized into two groups; of 186 normospermic and 92 OAT patients according to World Health Organization 2010 criteria Each participant provided informed consent prior to launching research Participants completed two general questionnaires of nutritional status Blood and semen samples were obtained for assessment, and all data were adjusted for age, body mass index (BMI), and season Vitamin D levels were classified according to Institute of Medicine guidelines Vitamin D deficiency, insufficiency, and normal levels were observed in 86%, 436%, 478% of participants, respectively No association was found between daily dietary intake of vitamin D and calcium with sperm parameters Serum vitamin D was inversely correlated with PTH (p < 0045) In normospermic men, serum vitamin D levels categorized were not correlated with semen parameters and reproductive hormones (FSH, LH, testosterone(T), and FT), whereas sperm motility showed a positive correlation with vitamin D categorized in OAT men (rs = 0131, p = 0028) In conclusion, there was a high incidence of deficiency and insufficiency 25(OH) D Levels (<20ng/ml) observed in Iranian men (522%) Moreover, our findings showed a correlation between vitamin D levels and sperm motility in OAT men, which requires further studies

https://onlinelibrary.wiley.com/doi/pdf/10.1111/andr.12280

Z. Zolfaghari

Papers

Association of vitamin D status with semen quality and reproductive hormones in Iranian subfertile men.