EXCLI Journal 2022;21:967-990 – ISSN 1611-2156

Received: April 09, 2022, accepted: June 24, 2022, published: July 20, 2022

Review article:

PIVOTAL ROLE OF VITAMIN D IN MITOCHONDRIAL HEALTH,

CARDIAC FUNCTION, AND HUMAN REPRODUCTION

Alavala Matta Reddy1 , Mumtaz Iqbal2 , Hitesh Chopra3 , Shaheda Urmi4 ,

Sunil Junapudi5 ,Shabana Bibi6,7* ,Santosh Kumar Gupta8 , Viajaya Nirmala Pangi9* ,
Inderbir Singh3 , Mohamed M. Abdel-Daim10,11
1
Department of Zoology, School of Life and Health Sciences, Adikavi Nannaya University,
Rajahmundry 533296, Andhra Pradesh, India
2
College of Arts and Science, University of South Florida, Tampa, FL33620, USA
3
Chitkara College of Pharmacy, Chitkara University, Punjab140401, India
4
Department of Pediatrics, Morsani College of Medicine, University of South Florida,
Tampa, FL33612, USA
5
Department of Pharmaceutical Chemistry, Geethanjali College of Pharmacy, Cherryal,
Keesara, Medchalmalkajgiri District, Telangana, 501301, India
6
Department of Biosciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan
7
Yunnan Herbal Laboratory, College of Ecology and Environmental Sciences,
Yunnan University, Kunming 650091, China
8
National Institute of Plant Genome Research, New Delhi 110067, India
9
School of Life and Health Sciences, Adikavi Nannaya University, Rajahamahendravaram,
Andhra Pradesh, India
10
Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College,
P.O. Box 6231 Jeddah 21442, Saudi Arabia
11
Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University,
Ismailia 41522, Egypt

* Corresponding authors: Shabana Bibi, Department of Biosciences, Shifa

Tameer-e-Millat University, Islamabad, Pakistan; Yunnan Herbal Laboratory, College
of Ecology and Environmental Sciences, Yunnan University, Kunming 650091, China.
E-mail: [email protected]
Viajaya Nirmala Pangi, School of Life and Health Sciences, Adikavi Nannaya University,
Rajahamahendravaram, Andhra Pradesh, India. E-mail: [email protected]

https://dx.doi.org/10.17179/excli2022-4935

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0/).

ABSTRACT
Vitamin D, a secosteroid hormone, appears to have significant beneficial effects on various physiological systems,
including the musculoskeletal system. Vitamin D assists in the regulation of numerous critical biological functions
and physiological processes in humans, including inflammation, oxidative stress, and mitochondrial respiration,
and is also linked to cardiac diseases. It is also reported that vitamin D plays a central role in molecular and cellular
mechanisms, which reduce oxidative stress, and tissue damage and regulate cellular health. On the other side,
hypovitaminosis D reduces mitochondrial activity and increases oxidative stress and inflammation in the body.
Hypervitaminosis D increases the prevalence and severity of cellular damage. It has also been reported that vitamin
D is involved in many functions of the reproductive system in human and critically play an important role in the
reproductive tissues of women and men. Its role is very well defined, starting from female menarche to menopause,

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pregnancy, and lactation, and finally in male fertility. Hence, the appropriate amount of vitamin D is necessary to
maintain the normal function of cell organelles. Based on recent studies, it is understood that vitamin D is involved
in the biological activities of mitochondria in cells, especially in cardiomyocytes. In this review, we emphasized
the role of vitamin D in mitochondrial respiration, which could significantly influence heart health and human
reproduction.

Keywords: Vitamin D, mitochondrial dysfunction, oxidative stress, cell damage, inflammation, cardiac diseases

INTRODUCTION Vitamin D levels of 50 nmol/L were

found to be insufficient in various clinical in-
Vitamin D is fat-soluble, linked to bone
vestigations and were linked to muscular at-
metabolism, and is well-known for its essen-
rophy and faintness (Tagliafico et al., 2010;
tial role in bones and skeletal muscle health
Van Langenberg et al., 2014). When exposed
(Halfon et al., 2015). Vitamin D is present in
to ultraviolet B rays, the human skin converts
bread, milk, fatty fish, mushrooms, and die-
7-dehydrocholesterol to vitamin D (Jäpelt and
tary supplements. As we know that there are
Jakobsen, 2013; Wacker and Holick, 2013).
two main forms of dietary or supplemental
The CYP P450 gene family has been ex-
vitamin D. These are vitamin D2 and D3. Vit-
panded to include numerous genes that play
amin D2 is derived from plants, while vitamin
pivotal roles in vitamin D activation and deg-
D3 comes from animals (fatty fish or sheep's
radation (CYP2R1, CYP27B1, and
lanolin). Both the forms are significant for
CYP24A1). Vitamin D initially hydroxylated
overall vitamin D levels. The biological roles
in the liver predominantly by the CYP2R1 en-
of vitamin D are very well defined. Cholecal-
zyme to produce 25-hydroxyvitamin D and
ciferol (known as vitamin D3) is bound to se-
then in the kidneys by another enzyme,
rum vitamin D-binding protein (DBP). For
CYP27B1, to produce 1α,25-dihydroxyvita-
the biological activation of vitamin D, two-
min D, which is the hormonally active form
step enzymatic pathways are necessary. These
are involving 25-hydroxylase of the liver and (Griffin et al., 2003; Bouillon et al., 2008;
1α-hydroxylase (CYP27B1) of the kidney and Saponaro et al., 2020).
extra-renal tissues. The majority of the func- Vitamin D is attached to its serum carrier,
tions are mediated by the VD receptor (VDR), vitamin D binding protein (DBP) in the
which is a ligand-dependent transcription fac- bloodstream. DBP is a highly polymorphic
tor. This transcription factor is primarily lo- protein that has at least 120 different
calized in the nuclei of target cells. VDR isoforms. Gc1f, Gc1s, and Gc2 are the three
works as a mediator for the genomic action of primary isoforms that have sparked the most
the biologically active hormone calcitriol interest. Their structural differences have an
impact on DBP function, which is linked to a
(1,25(OH)2D3). Calcitriol is an active form of
large number of clinical aspects. Studies con-
vitamin D, which is produced by the hydrox-
firm that polymorphism of specific DBP
ylation of 25(OH)D in kidneys under the reg-
isoforms leads to a lower level of circulating
ulation of parathyroid hormone (PTH) and se-
DBP (Santos et al., 2019). Serum calcium lev-
rum calcium. This form acts as an inducer for
els have been reported to be normal in patients
the transcription of more than 900 genes
with low levels of circulating DBP. The pri-
(Minghetti and Norman, 1988). VDR receptor
mary role of DBP is to keep a stable reservoir
is widely distributed over various tissues and
of circulating extracellular vitamin D metab-
organs including skeletal muscles, parathy-
olites in place. DBP is more effective in this
roid glands, and the reproductive tissues. This
role than albumin due to its stronger affinity
indicates that various metabolic processes are
for vitamin D metabolites, even though both
regulated by VDR, significantly (Kinuta et
DBP and albumin are filtered into urine and
al., 2000) as shown in Figure 1.
retrieved by megalin.

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Figure 1: Vitamin D metabolism of human; an overview

Under normal physiological conditions, and activation of vitamin D-responsive ele-

1α,dihydroxyvitamin D binds to its nuclear ments and trigger various second messenger
receptor, the vitamin D receptor (VDR), and systems (Gil et al., 2018). Vitamin D defi-
then to a retinoid X receptor (RXR), forming ciency raises the risk and severity of several
a VDR-RXR heterodimer that interacts with diseases, including obesity, insulin resistance,
regulatory elements in the genome and regu- type 2 diabetes, hypertension, pregnancy is-
lates the transcription (Haussler et al., 1997). sues, memory difficulties, osteoporosis, auto-
VDR is a transcription factor that has been immune diseases, malignancies, and systemic
shown to influence the expression patterns of inflammatory illnesses (Garcia-Bailo et al.,
many genes (Khammissa et al., 2018). The in- 2011; Berridge, 2017a; Szymczak-Pajor et al.,
teraction of 1α,25-dihydroxyvitamin D with 2020).
its intracellular receptors is also known to af- The Endocrine Society recommends a
fect vitamin D–dependent gene transcription daily dose of 400 IU of vitamin D for children

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aged 0 to one year and 600 IU for children vitamin D, regulation of 25-hydroxyvitamin
aged one to eighteen years. The Society ad- D metabolites in the liver, the definition of
vises 1500-2000 IU for men and women over hypervitaminosis of D, hypovitaminosis in
18 years old, including nursing and pregnant acute illness, requirements of vitamin D dur-
women whose newborns are not getting ing reproduction, cellular and organ activities
enough vitamin D (Endocrine Society, 2017). under vitamin D receptor influence, and pos-
Vitamin D deficiency/insufficiency is a pub- sible links between vitamin D and major dis-
lic health problem because it is independently eases (Minisola et al., 2019; Giustina et al.,
connected with a greater risk of all-cause 2020). Keeping vitamin D levels in an optimal
mortality. Vitamin D3 therapy with a daily range allows it to improve several processes
dose of 500 U reduced the frequency of res- while avoiding the complications associated
piratory infections by two-thirds in patients with overdose. The vitamin D fluctuation is
with 25-hydroxyvitamin D levels less than 20 widely associated with several diseases, in-
ng/ml, which typically leads to impaired ab- cluding cardiovascular diseases (Ohsawa et
sorption of vitamin D. Vitamin D sufficiency, al., 2000; Brewer et al., 2011), cancer
a serum 25-hydroxyvitamin D level of at least (Hammad et al., 2013; Weinstein et al., 2015),
30 ng/mL reduced the risk for adverse clinical immune system disorders (Jeffery et al., 2015;
outcomes in patients with COVID-19 infec- Wang et al., 2017), diabetes (Al-Timimi and
tion (Maghbooli et al., 2020). Hypovitamino- Ali, 2013), neuropsychiatric disorders (Kesby
sis D was associated with a decline in muscu- et al., 2011) and several other diseases. The
lar function and performance and increased central focus of this review is to explore the
disability (Berridge, 2017b; D’Amelio and potential of vitamin D, its association with
Quacquarelli, 2020). Vitamin D supplementa- mitochondrial dysfunction, oxidative stress,
tion has been shown to boost muscle strength cellular damage, inflammation, and immune
and speed in aged people (Halfon et al., 2015; system (Jeffery et al., 2015), calcium homeo-
Berridge, 2017b). Vitamin D supplementa- stasis linked with vitamin D, and cardiac dis-
tion has been linked to a lower risk of falls due eases (Figure 2).
to direct effects on muscle cells (Ramasamy,
2020; Wilson-Barnes et al., 2020). On the ROLE OF VITAMIN D IN MITOCHON-
other hand, excessive vitamin D levels might DRIAL FUNCTION/DYSFUNCTION
have harmful effects, such as kidney stones, Mitochondria are cell organelles with
renal impairment, malignancy, and possibly outer and inner membranes, though the inner
some indications of cardiovascular disease membrane forms many folds known as cristae
(CVD), especially when combined with a (Ashcroft et al., 2020). The intermembrane
high calcium intake (Brouwer-Brolsma et al., space refers to the space between the outer
2013). and inner membranes, while the matrix refers
The research focus on vitamin D has ex- to the space within the inner membrane
panded beyond its recognized classic bone (Ashcroft et al., 2020). The mitochondria pro-
health benefits, including diabetes and cardi- duce energy in the form of ATP. The reduc-
ovascular, neurological, pulmonary, renal, tion in ATP production is independent of
and liver illnesses. Yet, several contradictory changes in many parameters of mitochondrial
discoveries continue to emerge (Stokes and machinery, including electron transport sys-
Lammert, 2016). However, some controver- tem (ETS) complexes I-V, citrate synthase,
sies and uncertainties still exist in certain as- and cytochrome C oxidase (Ashcroft et al.,
pects related to a daily dose of vitamin D re- 2020). After the step-by-step transmission of
quired in the general population to maintain electrons, the mitochondrial matrix actively
normal levels of 25-hydroxyvitamin D, sup- pumps hydrogen ions into the intermembrane
plementation for metabolic bone diseases, ul- space. ATP synthase returns protons from in-
traviolet-B induced cutaneous production of

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termembrane space to the mitochondrial ma- 2017). In particular, the synthesis of ATP is
trix by passing them across an electrochemi- reduced because of the decrease in vitamin D-
cal gradient process. ATP is synthesized by dependent development of the electron
coupling proton translocation with phosphor- transport chain complex I. Ashcroft et al.,
ylation of ADP. (2020) found that VDR is required to main-
tain mitochondrial respiration at an optimal
level in myoblasts and myotubes (Ashcroft et
al., 2020). The reduction in mitochondrial res-
piration in VDR-deleted myoblasts and myo-
tubes as a result of reduced ATP. Further, vit-
amin D has no effect on mitochondrial ETC
subunit I–V, citrate synthase, or cytochrome-
c protein content in VDR-KD myoblasts and
myotubes (Ashcroft et al., 2020). The de-
crease in maximum oxidant ability without
any alterations in ETS I-V protein expression
was reported in an in vivo study with mice de-
prived of vitamin D (Habib et al., 2020).
Most of the vitamin D research in humans
focuses on protein synthesis and breakdown.
There is growing evidence that vitamin D
supplementation improves mitochondrial
density and function (Sinha et al., 2013; Rana
et al., 2014). Vitamin D supplementation en-
hances the balance between synthesis and
breakdown of muscle protein, as well as mi-
tochondrial density in an in vivo rat model
Figure 2: Vitamin D and potential linkage with crit- study (Gogulothu et al., 2020). To accomplish
ical biological functions, cardiac and mitochon- the immediate and intensive energy demands
drial diseases during exercise, the muscle stores phospho-
creatinine (P-creatinine) (Bouillon and
In addition to impacting muscle mass and Verstuyf, 2013). P-creatinine is the muscle’s
functionality, evidence suggests that vitamin inorganic phosphate content. In vitamin D de-
D in skeletal muscles may influence mito- ficient patients, P-creatinine levels were de-
chondrial activity. In the case of vitamin D creased. However, it was restored after vita-
deficiency, mitochondrial respiration dimin- min D treatment and exercise in randomized
ishes with a reduction in nuclear mRNA and clinical trials (Wagner et al., 2013). The
protein (Kim et al., 2014). When 1,25-dihy- slower rate of energy generation in the mito-
droxyvitamin D3 was administered to human chondria of skeletal muscle could lead to a
primary myoblasts, mitochondrial activity loss of muscle strength and a fast feeling of
improved, and the number of mRNAs encod- exhaustion during moderate activity (Latham
ing mitochondrial proteins increased by al- et al., 2021). P-creatinine is broken down dur-
most 80 percent (Ryan et al., 2016). Vitamin ing muscle contraction and generates creatine.
D is needed to sustain the functioning of the The P-creatinine system generates a lot of
mitochondrial respiratory chain (Consiglio et ATPs, which is crucial when metabolic de-
al., 2015). The synthesis of the uncoupling mand is high, such as during intense aerobic
protein (UCP), which regulates thermogene- exercise, and other metabolic pathways can-
sis on the internal mitochondrial membrane, not keep up with the need. In essence, P-cre-
is similarly affected by vitamin D (Abbas,

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atinine fosters the short-term high level of en- ternal membrane fusion, resulting in im-
ergy needed during intense exercise. Ye et al. proved mitochondrial oxidative capacity
(2001) observed a decrease in the P-creatinine (Kushnareva et al., 2013). The OPA1 protein
/ATP ratio in a pig model of congestive heart expression was elevated with 1,25-dihy-
failure (Ye et al., 2001). Further, research droxyvitamin D treatment in vitamin D defi-
shows that P-creatinine system damage oc- cient mice with statin-induced myopathy and
curs before contractile dysfunction, which re- human skeletal muscle cells (Ryan et al.,
duces the energy reserve (Ingwall and Weiss, 2016; Ren et al., 2020). Ricca et al. (2018)
2004). Vitamin D could reverse P-creatinine studied the in vitro function of mitochondria
fluctuation in contractile function by restoring by silencing VDR and reported the enhanced
mitochondrial function, and this could be a respiratory activity in silenced cells that was
potential research target for further investiga- associated with increased reactive oxygen
tion. Furthermore, the activation of the vita- generation (ROS). The absence of the recep-
min D receptor protein has been confirmed to tor eventually led to mitochondrial malfunc-
increase serum creatinine. Concern regarding tion and cell death and slowed down cellular
this fact is that while serum creatinine levels proliferation. These results indicate that VDR
are increased, the glomerular filtration rate protects cells against excess breathing and
decreases. However, a study found results to ROS production that cause cell damage (as
the contrary. The short-term activation of vit- shown in Figure 3) (Ricca et al., 2018).
amin D receptors increases serum creatinine
levels along with overall creatinine produc-
tion and generates no detrimental effects on
the glomerular filtration rate (Agarwal et al.,
2011).

The role of vitamin D receptors in

mitochondrial function
The ubiquitous nature of VDR suggests
the possibility of extensive impacts, prompt-
ing further research into the effects of vitamin
D in several tissues in the human body
(Omdahl et al., 2002). In genomic results,
VDR activation in the nucleus leads to cellu-
lar differentiation and proliferation
(Sirajudeen et al., 2019). Nongenomic effects
leading to fast calcium influx within muscle
cells could be attributed to a potential trans-
membrane receptor (Rebas et al., 2017).
1,25-dihydroxyvitamin D controls the ox-
idative capacity by avoiding substantial
changes in the density or amount of ETS pro-
tein. A recent study revealed that VDR knock- Figure 3: Effect of deficiency of vitamin D3 caus-
down (VDR-KD) in myotubes of C2C12 en- ing protein degradation and muscle atrophy
hances the synthesis of mitochondrial fusion
protein optic atrophy 1 (OPA1), which has
Furthermore, a similar study by Ricciardi
been proposed as a compensatory strategy for
et al. (2015) found that vitamin D and VDR
restoring mitochondrial function (Ashcroft et
signaling decreases mitochondrial respira-
al., 2020). In mitochondria, OPA1 causes in-
tion, serving as an important regulator for

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many essential bioenergetic metabolic path- The lack of VDR leads to a decrease in
ways. The ability of vitamin D/VDR to regu- cell proliferation, which is highly required
late mitochondrial respiration allows the mi- during the cells that acquired higher VDR in
tochondria to adapt to various metabolic the G0 and G1 phases of the cell cycle than in
states that arise during times of cell growth, the M phase (Consiglio et al., 2014). Consig-
signaling, and proliferation (Silvagno and lio et al. (2014) found that cancer cells with
Pescarmona, 2017). To continue, the study silenced VDR have decreased the rates of pro-
conducted by Silvagno and Pescarmona liferation, leading to the hypothesis that re-
(2017) found that KO VDR mice have shown duced VDR expression could be a possible
deficient calcium absorption leading to hy- cancer treatment. Silencing of VDR increased
pocalcemia, hypophosphatemia, secondary cytochrome C oxidase subunits II and IV tran-
hyperparathyroidism, osteomalacia, and rick- script. VDR silencing inhibited the mevalo-
ets. The same study also identified VDR as a nate pathway and histone acetylation levels,
mitochondrial energy expenditure regulator which are acetyl CoA-dependent biosynthetic
due to the finding that VDR KO mice have pathways (Consiglio et al., 2014). Inhibiting
shown higher basal energy expenditure rates histone acetylation decreases gene transcrip-
and increased levels of energy up-coupling in tion levels, and since acetyl CoA is a key mol-
the form of the electron transport chain in mi- ecule in metabolism, various pathways have
tochondria. Additionally, VDR KO mice the potential to be affected by VDR. These
were found to have a debilitating effect on the findings suggest that VDR regulates the mito-
skin in regards to decreasing the efficiency of chondrial respiratory chain activity, the ace-
the barrier to a host of pathogens via disrup- tyl-CoA pathway, the TCA cycle, and biosyn-
tion in the processes of lipid composition and thetic pathways of cell development.
secretion that help make the barrier effect. Researchers investigated the significance
The VDR protein was discovered with of vitamin D in maintaining the in vivo activ-
two anti-VDR antibodies, and the mitochon- ity of mitochondria by utilizing a known diet-
drial VDR disappeared by the VDR gene si- induced vitamin D deprivation model in mice
lencing in immortalized human keratinocytes C57BL/6J. The study with a diet-induced vit-
(Consiglio et al., 2014). VDR localization in amin D deficiency model of mice(C57BL/6J)
mitochondria needs a specific mitochondrial results in reduced mitochondrial respiration in
import mechanism involving the import of skeletal muscle that could lead to muscle fa-
cholesterol or the export of cytochrome C tigue and performance deficits (Ashcroft et
(Silvagno et al., 2013). It's unclear how mito- al., 2021). Vitamin D (calcitriol) increases in-
chondrial VDR affects gene expression, cat- tramyocellular lipid (IMCL) accumulation
ion control, oxidative function, and tissue- and oxygen consumption rate, which is driven
specific activity in platelets or muscles. It also by mitochondrial complex II in C2C12 myo-
regulates several other nuclear receptors in tubes, and this increase is at least partially me-
mitochondria including estrogens, glucocorti- diated by a protein, Perilipin 2 (PLIN2)
coids, and thyroid hormone receptors (Psarra (Schnell et al., 2019). Kolleritsch et al. (2020)
et al., 2006). Mitochondria are generally reported that the low cardiac perilipin is
acknowledged as having a function in form- linked to reduced mitochondrial fission and
ing reactive nitrogen, reactive oxygen species could be used to inhibit the emergence of lipo-
(ROS), and antioxidants. The antioxidants' toxic cardiomyopathy (Kolleritsch et al.,
defense mechanisms were shown to be en- 2020). An increase in myocardial lipid stor-
hanced in rickets (Doǧan et al., 2012). Both age and decreased cardiac performance were
metabolic and osteoporosis syndrome is asso- observed after myocardial infarction in peo-
ciated with oxidative stress (Manolagas, ple with PLIN2 deficiency(Mardani et al.,
2010). 2019).

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VITAMIN D, MITOCHONDRIA, AND end of the study, all participants have de-
CARDIAC DISEASES creased levels of plasma renin and aldoste-
rone (Carrara et al., 2014). These findings can
Cardiovascular diseases, including heart
potentially improve outcomes for patients
failure, aortic aneurysmal heart disease, pe-
with hypertension. Furthermore, a novel
ripheral artery disease, hypertension and ath-
study by Tomaschitz et al., confirmed this by
erosclerosis, coronary artery disease, myocar-
concluding that lower vitamin D levels corre-
dial infarction, hypertrophy, cardiomyopathy,
late to an upregulation of the renin-angioten-
and cardiac fibrosis, are significant causes of
sin-aldosterone system, inevitably leading to
morbidity and mortality (Drazner, 2011; Rai
hypertension (Tomaschitz et al., 2010). This
and Agrawal, 2017; Elgendy et al., 2019).
provides evidence for vitamin D has a strong
These illnesses are linked to low levels of vit-
effect on both the cardiovascular and renal
amin D, and supplementing with vitamin D is
systems. To continue, Diez et al. tested a daily
an effective treatment option (Wang et al.,
dose of 30 ng/kg of vitamin D in a modified
2008). Myocardial infarction is the prominent
VDR ischemia-reperfusion (I/R) rats model.
cause of morbidity and mortality in the world.
They also found reversed ischemia-reperfu-
Lee et al., reported that vitamin D3 inhibits
sion changes by restoring myocardial vitamin
oxidative stress and regulates mitochondrial
D receptor levels and prolonging action po-
activity to reduce hypoxia/reoxygenation
tentials (Diez et al., 2015). Lack of VDR
(H/R)-induced apoptosis in a mouse model
causes increased left ventricle (LV) mass and
(Lee et al., 2020). They also stated that vita-
elevated levels of atrial natriuretic peptide
min D3 exerts cardioprotective effects and re-
coupled with an imbalance of homeostasis,
verted H/R-induced mitochondrial fission and
and metalloproteases of heart and fibroblasts.
mitophagy by inhibiting mitochondrial fis-
These findings suggest that vitamin D defi-
sion proteins, phosphorylated dynein-related
ciency may be associated with vascular dys-
protein 1 (pDrp1), and mitochondrial fission
function, arterial steadiness, and enlargement
factor (Mff) (Lee et al., 2020). Mitochondrial
of the LV. Sufficient or insufficient vitamin D
fusion and fission are dynamic events, which
levels may have a role in the development of
play a significant role in mitochondrial and
cardiovascular disease (Khan et al., 2016).
cellular quality control processes (Youle and
VITAL (VITamin D and OmegA-3 TriaL)
Van Der Bliek, 2012). In mitochondrial fu-
and ViDA (Vitamin D Assessment) are two
sion, two small healthy mitochondria fuse and
extensive, randomized control studies con-
form a mitochondrion that can produce ATP
ducted to study the effects of vitamin D sup-
for cellular function. In another way, the dam-
plementation on CVD outcomes (Manson et
age to mitochondria by fission and mitophagy
al., 2012; Scragg, 2020). The VITAL is a ran-
will be eliminated (Westermann 2010; Youle
domized clinical trial with 25,871 US subjects
and Van Der Bliek 2012; Chidipi et al., 2021).
who found that daily dietary supplementation
Vitamin D receptors are expressed in the car-
of vitamin D3 (2000 IU) or omega-3 fatty ac-
diovascular system and activated by modulat-
ids (1 gram) reduces the risk of cancer devel-
ing the renin-angiotensin system, inflamma-
opment, heart disease, and stroke in people
tion, and fibrosis against myocardial hyper-
without previous history of these illnesses
trophy and hypertension (Gardner et al.,
(Manson et al., 2012). ViDA study found that
2013). The renin-angiotensin-aldosterone
vitamin D supplementation does not affect the
system is especially susceptible to vitamin D
primary outcomes such as cardiovascular dis-
since it negatively regulates renin and is cor-
ease, acute respiratory infections, non-verte-
related with a decrease in blood pressure and
bral fractures, falls, and all cancers (Scragg,
left ventricular hypertrophy. In a study by
2020).
Carrara et al., patients with hypertension and
vitamin D deficiency were given a weekly
dose of cholecalciferol for two months. At the

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Effect of vitamin D on oxidative stress perpolarization is regulated by cGMP-de-

Increased ROS levels cause oxidative pendent protein kinases, which limit cytosolic
stress. During myocardial ischemia/reperfu- calcium flow by enhancing calcium-depend-
sion (I/R), mitochondria generate ROS as a ent potassium opening and cell hyperpolariza-
result of aerobic metabolism (Chouchani et tion (Koh et al., 1996). Hu et al. investigated
al., 2014). Vitamin D3 can boost endothelial the mechanisms involved in the inhibition of
cell proliferation and suppress apoptosis via myocarditis by vitamin D in experimental au-
increasing endothelial nitric oxide synthase toimmune myocarditis (EAM) mice model
(eNOS) expression and nitric oxide (NO) pro- (Hu et al., 2016). The treatment of vitamin D
duction (Molinari et al., 2013). The phosphor- reverted left ventricular dysfunction (ejection
ylation of NOS in the heart is a crucial adjunct fraction and fractional shortening), apoptosis,
for myocardial perfusion following ischemia and autophagy (Hu et al., 2016). It is also
and myocardial contractility, oxygen con- known that vitamin D may improve heart
sumption, hypertrophic remodeling, apopto- function by suppressing inflammatory cardiac
sis, and myocardial regeneration in cardiac infiltrations, lowering apoptosis of cardiomy-
cells (Ahmad et al., 2018; Farah et al., 2018). ocytes, and modulating autophagy (Hu et al.,
NOS also improves the anticoagulant and 2016). Even though research has linked ROS
anti-thrombogenic capacity of vascular endo- to heart tissue damage, there is no cure at pre-
thelium, maintains vascular tone, and pre- sent (Figure 4). Further studies may yield new
vents the proliferation of vascular cells therapeutic insights for I/R (Granger and
(Rajendran et al., 2013). Nitric oxide controls Kvietys, 2015). Furthermore, vitamin D has
various signaling molecules such as soluble the potential to combat oxidative stress not
guanylate (sGC), cytochrome C oxidase, and only in cardiac myocytes but also in photore-
hemoglobin by binding it to iron heme in the ceptors of the eye. In a study conducted by
metalloproteins (Tsai et al., 2012). The inter- Tohari et al., mouse cone cell lines were sub-
action of NO with heme of sGC in smooth jected to oxidative stress and then given a vit-
muscle cells near the endothelium catalyzes amin D treatment (Tohari et al., 2016). The
guanosine triphosphate (GTP) into guanosine results showed that the oxidative stress in the
monophosphate (cGMP), which is the pri- cone cells was reversed and this finding has
mary mechanism for the NO action (Tsai and the potential to impact human patients with
Kass, 2009). Smooth muscle membrane hy- photoreceptor diseases.

Figure 4: Vitamin D links mitochondrial dysfunction and the consequences on major biological pro-
cesses and functions.

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Vitamin D and inflammation ficiency, macrophagic cholesterol uptake oc-

Vitamin D metabolites affect immune and curs and is finally deposited into endothelial
inflammatory cell differentiation and produc- spaces, which promotes atherosclerosis
tion of cytokines, which means vitamin D me- (Pludowski et al., 2013; Cyprian et al., 2019).
tabolites play an essential role in the develop- Diminished high-density lipoproteins and
ment of atherosclerosis and other vascular in- apolipoprotein A-1 ratios, that cause athero-
flammation-related disorders (Martens et al., sclerosis, were combined with a deficiency in
2020). 25-hydroxyvitamin D and its active vitamin D (Weng et al., 2013). Vitamin D ef-
hormonal form, 1,25-dihydroxyvitamin D, fectively reduces the intracellular NF-κB lev-
are required for human physiological pro- els to reduce atherosclerosis development
cesses, including reducing inflammation and (Legarth et al., 2019). Mitochondrial dysfunc-
intracellular oxidative stress. Vitamin D is a tions were detected in atherosclerosis, includ-
crucial regulator of systemic inflammation, ing downregulation of mitophagy similar to
oxidative stress, and mitochondrial respira- autophagy, which can eliminate the damaged
tory function in humans, as well as the aging part of the mitochondria (Yang et al., 2020;
process (Bhatti et al., 2017). Vitamin D defi- Poznyak et al., 2021) (Figure 4). However, it
ciency and atherosclerosis are both common is unclear whether vitamin D regulates mito-
diseases and there is reason to believe that a chondrial dysfunction in atherosclerosis de-
correlation exists between the two. Athero- velopment (Mandarino et al., 2015; Poznyak
sclerosis is characterized as a lipid storage et al., 2021). Moreover, VDR being found on
disease known as vascular wall inflammation various tissue types, including brain and pan-
(Kim et al., 2008; Marchio et al., 2019; creas tissue, links vitamin D and cardiovascu-
Wimalawansa, 2019). The lipids have been lar diseases such as atherosclerosis and hyper-
deposited, and T-cells and macrophages are tension stronger (Menezes et al., 2014). In ad-
accumulated due to the endothelium reaction dition to the direct relationship between vita-
(Mosser and Edwards, 2008; Gibson et al., min D deficiency and heart disease, the defi-
2018). Reactive oxygen species are of central ciency can indirectly exacerbate cardiac
importance, which may lead to the oxidation symptoms by interfering with endocrine pro-
of lipids, including low-density lipoproteins cesses that impact cardiac function. One ex-
and polyunsaturated fatty acids, which are de- ample of this indirect link is the ability of vit-
posited in the vascular wall, and harm cellular amin D to decrease insulin resistance, which
components directly (Leopold and Loscalzo, ultimately benefits patients with atherosclero-
2008; Rafieian-Kopaei et al., 2014). Nitric sis and hypertension by decreasing the activ-
oxide, mentioned previously, serves a protec- ity of lipoprotein lipase, leading to a decrease
tive function in the endothelium. Interest- in the level of lipoproteins and LDLs in the
ingly, vitamin D increases endothelial nitric blood (Menezes et al., 2014).
oxide thereby helping to maintain the vascu-
lature and avoid atherosclerosis (Menezes et Vitamin D and calcium homeostasis
al., 2014). Vitamin D deficiency is common Vitamin D deficiency has been associated
globally and seems to be implicated in several with an increased mortality rate, particularly
stages in the pathophysiology of atherosclero- cardiovascular mortality (Heath et al., 2019).
sis (Kassi et al., 2013; Latic and Erben, 2020). The calciotropic hormones, including vitamin
Atherosclerotic lesions are generated that D, parathyroid hormone, and calcitonin, are
may rupture and lead to vascular lumen responsible for maintaining calcium homeo-
blockage via the activity of multiple cytokines stasis within normal ranges (Mundy and
(Lusis, 2000; Badimon et al., 2012). Vitamin Guise, 1999). Vitamin D regulates intracellu-
D suppresses the absorption of cholesterol by lar calcium and ROS (Duchen, 2000). The
macrophages, and in the case of vitamin D de- fluctuation of intracellular calcium regulates
mitochondrial calcium and health (Bagur and

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Received: April 09, 2022, accepted: June 24, 2022, published: July 20, 2022

Hajnóczky, 2017). Cardiac cell contractual body, and the regular dietary calcium intake
characteristics are primarily regulated by the helps regulate the metabolism of vitamin D
direct contact with the calcium, known as the (Fleet, 2017). The primary role of vitamin D
calcium-induced calcium release mechanism is in regulating intestinal calcium absorption,
(Eisner et al., 2017). The cardiac contractile urinary calcium excretion, and bone metabo-
proteins, actin, and myosin are regulated by lism. To achieve this goal, these regulatory
the intracellular levels of calcium (Rüegg, events occur in coordination with numerous
1998; Kuo and Ehrlich, 2015). The extracel- tissues, including the intestine, kidney, bone,
lular homeostasis of calcium influenced by and parathyroid gland (Fleet, 2017; Bhattarai
vitamin D alters intracellular calcium and et al., 2020).
may impact heart cell contractility indirectly
(Weber et al., 2008). Pfeifer et al. studied
VITAMIN D AND REPRODUCTIVE
older women with vitamin D deficiency who
HEALTH
were supplemented with calcium and 20 μg of
vitamin D3 as a daily dose and found an in- The link between vitamin D and human
crease in serum 25-hydroxyvitamin D of 20 reproduction is precious. There are two types
nmol/l, a 9.3 % de-crease in systolic blood of effects covered under vitamin D levels and
pressure, and a 5.4 % decrease in heart rate their effects on human organs. These are clas-
compared with those supplemented with cal- sical and non-classical effects (Figure 5).
cium alone (Pfeifer et al., 2001). They also There are several reports available on the
concluded that vitamin D3 and calcium intake proven vital link between vitamin D levels
could contribute to the pathogenesis and pro- and reproductive health in humans.
gression of hypertension and cardiovascular
disease in older women (Pfeifer et al., 2001). Role in the female reproductive system
The alteration of intracellular calcium could The pivotal role of vitamin D is well stud-
affect the mitochondrial function via VDR. ied in the female reproductive system. There
Vitamin D regulates mitochondrial calcium are three important phases of reproductive
homeostasis. Mitochondrial calcium has addi- women’s life span. These are menarche, ado-
tional vital functions, such as mitochondrial lescence, reproductive period, and meno-
metabolic control, ATP generation, and cell pause. Poor vitamin D status in the develop-
death (Giorgi et al., 2012). Another clinical ing stage is a serious matter of concern as it is
study with 3258 participants showed that se- critical for optimal bone mineral status in the
vere and moderate vitamin D deficiency (19.0 developing skeleton. Literature suggested that
and 33.3 nmol/l) leads to a higher rate of car- the Dietary Reference Intake (DRI) is very
diovascular death compared to the patients poorly distributed among growing girls. It
with normal levels (71.0 nmol/l) over 7 years was found that a total of 50 % of girls aged
(Murr et al., 2012). between 9–13 years and 32 % of girls aged
The endocrine hormone 1,25-dihy- between 14–18 years are only meeting the
droxyvitamin D is produced in response to di- recommendation for vitamin D (200 IU/d or 5
etary calcium intake and physiologic states mg/d) (Moore et al., 2004). In adolescents,
such as growth, aging, and menopause (Fleet, this deficiency leads to decreased absorption
2017). Most of the molecular activities of of dietary calcium which results in an altered
1,25-dihydroxyvitamin D on calcium-regulat- form of the growth and poor mineralization of
ing target tissues are mediated via transcrip- the skeleton. Sometimes this deficiency leads
tion regulated by the vitamin D receptor (Pike to the generation of secondary hyperparathy-
and Christakos, 2017). Calcium homeostasis roidism, and a higher risk of developing bone
may be controlled by blood calcium levels of abnormalities (Holick, 2004). Vitamin D
the necessary ranges, vitamin D endocrine plays a critical and potential role in the mod-
regulates the total calcium homeostasis of the ulation of obesity, energy metabolism, and

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Figure 5: Classical and non-classical effects of vitamin D on human health

insulin secretion in adolescent stage of fe- well known that the timing of menarche gen-
males (Skinner et al., 2003). Another aspect erally depends on temperature, sun exposure,
of vitamin D deficiency is linked with puberty and socioeconomic status in society, but in
which is a time of dramatic developmental some ways it is directly related to a geo-
changes in the body in a sequential manner to graphic gradient of specific sun exposure hab-
reach mature adult reproductive stages. It is its, ultimately leading to vitamin D status at

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 EXCLI Journal 2022;21:967-990 – ISSN 1611-2156
Received: April 09, 2022, accepted: June 24, 2022, published: July 20, 2022

this stage. Hence, we can conclude that vita- In the case of follicular development stud-
min D status is linked with menarche. Finally, ies, it has been concluded that vitamin D
vitamin D status could indirectly affect the might promote the differentiation and devel-
timing of menarche through its effect on obe- opment of human granulosa cells, thus play-
sity in developing girls. Some physiological ing an important role in human follicular de-
and biochemical pathways might play an im- velopment (Merhi et al., 2008, 2012, 2014;
portant role in secretion of adipose-derived Merhi, 2009; Irani and Merhi, 2014).
hormones, but it is unclear whether these hor- Most of the sex hormones are derived
mones derived from adipose tissues could al- from cholesterol which works as the common
ter in response to vitamin D supplementation precursor and can be obtained either through
or not (Yura et al., 2000; Maetani et al., 2009; dietary supplements or de novo synthesized
Donoso et al., 2010). It was reported that In- from acetyl CoA. The production process of
sulin-like growth factor-1 (IGF-I) may regu- these hormones is controlled by multiple en-
late the releasing of sex hormones. Vitamin D zymes. It was evident from published reports
receptors have been shown in different parts that the expression and activity of some of
of the brain including the hypothalamus thus these enzymes were affected by vitamin D
it may be positively related to the age at men- (Merhi et al., 2014). It was also found that in
arche, and its insufficiency was associated human ovarian cells, the production of vital
with earlier menarche through neuroendo- hormones like progesterone, estrogen, es-
crine regulation of the gonadotropic axis trone, and insulin-like growth factor-binding
(Zhen et al., 1997; Eyles et al., 2005; DiVall protein 1 has increased under the direct influ-
and Radovick, 2008; Breen et al., 2011; ence of vitamin D levels. It was also reported
Villamor et al., 2011). that 1,25-dihydroxyvitaminD3 strongly stim-
It was reported that vitamin D regulates ulated the production of the hormones estro-
the expression of a large number of genes in- gen and progesterone in the human placenta
volved in the reproductive tissues of the fe- (Barrera et al., 2007).
male reproductive system. Several tissues of It was reportedin the case of female rats
the endocrine and reproductive system are that a low level of vitamin D leads to a 75 %
having VDR. In females, vitamin D is criti- decrease infertilitywhich further leads to
cally involved in the physiological functions complications in pregnancy. Sometimes, this
of ovarian follicles. It was studied that human deficiency may link with uterine hypoplasia
ovaries contain granulosa cells. The nuclei and impaired folliculogenesis. Calcium ho-
and cytoplasm of these cells are abundantly meostasis is maintained by vitamin D suffi-
containing vitamin D receptors. This indicates cient level in the reproductive phase which fi-
that vitamin D plays an important role in the nally modulates the estrogen biosynthesis
female reproductive system (Thill et al., (Panda et al., 2001; Sun et al., 2010; Wojtusik
2009).Thus, we can say that vitamin D defi- and Johnson, 2012). Calcium repaired fertility
ciencies directly or indirectly play role in is- was studied in the case of animals which was
sues of subfertility, endometriosis, polycysti- achieved by vitamin D and a diet supple-
covary syndrome (PCOS), preeclampsia, pre- mented (Johnson and DeLuca, 2001;
term delivery, gestational diabetes, and bacte- Anagnostis et al., 2013).
rial vaginosis. Hence, optimal vitamin D lev- Pregnancy and lactation are two very pre-
els in the reproductive phase and throughout cious stages for every female. It was reported
a woman’s life are always important. It was that the active form of vitamin D was highly
also reported that vitamin D induces some- required to increase the intestinalabsorption
how the secretion of important hormones pro- of calcium and the mobilization of maternal
gesterone, estrone, and estradiol secretion in bones. A total of approximately 30 g of cal-
ovarian cells either independently or syner- cium is absorbed by human embryos. Skele-
gistically with insulin. ton contains 99 % of this calcium. Almost 150

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 EXCLI Journal 2022;21:967-990 – ISSN 1611-2156
Received: April 09, 2022, accepted: June 24, 2022, published: July 20, 2022

mg/kg/day of calcium is transferred by pla- 2007; Zipitis and Akobeng 2008; Mirzaei et
centa during the last trimester of pregnancy al., 2011).
(Kovacs, 2008). Vitamin D deficiency is
prevalent among pregnant women. It was re- Vitamin D levels and their role in infertility
ported during pregnancy stages, increase in Approximately 15 % of the couples are
the plasma vitamin D levels could contribute severly affected by infertility disorders due to
to the reductionin plasma calcium level and poor level of vitamin D. These are due to the
may result from increased metabolism of various problems like polycystic, ovary syn-
mothers or increased utilization of vitamin D drome, endometriosis infertility, myoma in-
by the fetus (Lerchbaum and Obermayer- fertility, male infertility, premature ovary fail-
Pietsch, 2012). ure. These problems can be cured by main-
It was studied that maternal vitamin D taining the normal levels of vitamin D. The
levels and the prevalence of bacterial vagi- literature demonstrates that low vitamin D
nosis among pregnant women are directly levels very often lead to PCOS compared to
linked with each other. Bacterial vaginosis women with normal levels (Li et al., 2011;
has been reported to disrupt the normal bal- Wehr et al., 2011). The deficiency is also
ance of vaginal flora, leading to increased linked with insulin resistance, obesity, and
growth of anaerobic bacteria responsible for metabolic syndromes. These are commonly
the secretion of inflammatory cytokines, pros- observed in PCOS which leads to ovulatory
taglandins, and phospho-lipase A2 (Allsworth dysfunction (Hosseinpanah et al., 2014).
and Peipert, 2007). Menstrual irregularity can be removed by
Calcium status plays a very critical role in proper supplementation of vitamin D. It might
the initiation of labor and also plays a role in be critically involved in improvement of fol-
smooth muscle function in early labor. The licular development, and pregnancy rate in
level of serum calcium is generally regulated women with PCOS (Rashidi et al., 2009; Ott
by vitamin D levels (Papandreou et al., 2004). et al., 2012).
Pregnant women with low levels (<37.5
nmol/l) of 25(OH)D3 delivered more than 4 Role in male reproductive system
times by cesarean section compared to Role of calcium is essential in the male re-
women with 37.5 nmol/l or greater with nor- productive system. This is highly required
mal delivery (Merewood et al., 2009). Vita- and crucial for spermatogenesis, and sperm
min D is essential for the maintenance of cal- motility. It was found that there is a direct role
cium homeostasis and a role in the initiation of vitamin D in semen quality and spermato-
of early labor. Vaginal delivery was severely genesis which works as a modulator of cal-
affected due to the poor maternal vitamin D cium metabolism.
status which might reduce the strength of the The basis of the interplay between vitamin
pelvic musculature in pregnant women D and reproduction lays on the presence of
(Scholl et al., 2012). Fetal development and both.
programming in pregnant women is directly In the rat, vitamin D receptors (VDR) and
linked with 3000 genes that are stimulated by 1α-hydroxylase (CYP27B1) have been re-
vitamin D levels (Kho et al., 2010). Mother ported to play important roles in various tis-
and child health is linked with normal vitamin sues of both sexes, but particularly in the rat
D levels. The deficiency during pregnancy of testis (Hirai et al., 2009). In case of human, it
vitamin D leads to chronic diseases in later was reported that VDR are found in testis, ep-
stages of child. Most of them are like wheez- ididymis, prostate, seminal vesicles, and
ing and asthma, schizophrenia, multiple scle- Leydig cells. Although when it was compared
rosis, type 1 diabetes mellitus, and insulin re- with others, the expression level was found
sistance (Altschuler, 2001; Hyppönen et al., different, which was slightly higher in epidi-
2001; Camargo et al., 2007; Devereux et al., dymis and seminal vesicles (Blomberg Jensen

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 EXCLI Journal 2022;21:967-990 – ISSN 1611-2156
Received: April 09, 2022, accepted: June 24, 2022, published: July 20, 2022

et al., 2010). Cholesterol efflux in human tors (Walters 1984). The key role of few en-
sperm was regulated by vitamin D molecules zymes is well established in the function of
which enhanced the sperm bioavailability. It vitamin D in various tissues. These enzymes
was studied that cytoplasm of epithelial cells are located either in the endoplasmic reticu-
of the epididymis and ductal prostate epithe- lum (ER) (e.g., CYP2R1) or in the mitochon-
lium was encountered with vitamin D recep- dria (e.g., CYP27A1, CYP27B1, and
CYP24A1) (Figure 6).

Figure 6: Vitamin D receptor (VDR) in both central and peripheral reproductive organs of both males
and females

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 EXCLI Journal 2022;21:967-990 – ISSN 1611-2156
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Meanwhile, it was reported that CYP2R1 sudden cardiac death and coronary illness. In
and CYPB1 play a very important role in all this review, we emphasized the potential role
tissues of the reproductive tract. CYPR1 gene of vitamin D in critical biological processes
expression might play some significant role in and the functions of explorations of the bio-
reducing testicular damage (Menegaz et al., logical components in mitochondrial-associ-
2009). It was supported by literature that the ated cardiac diseases.
number and motility of sperm was directly In summary, vitamin D supplementation
linked with the protective effect of vitamin D in humans plays a significant role in support-
from oxidative stress and cellular toxicity ing mitochondrial health and regulating car-
(Kägi et al., 1988). Vitamin D plays a crucial diac disease progressions. Detailed mechani-
role in the process of spermatogenesis and cal inquiries are necessary to light the mani-
steroidogenesis through the induced expres- festation of vitamin D in mitochondrial func-
sion of calcium-binding protein CaBP28k in tion and cardiac health.
the testis (Shahbazi et al., 2011). Recently, it
was reported that severe hypo-spermatogene- Author contributions
sis or idiopathic sertoli cell-only syndrome Conceptualization, writing - original draft
(SCOS) in males was directly linked with preparation was performed by A.M.R.; M.I.;
lower plasma 25(OH)D concentrations de- S.U.; S.J.; and S.K.G.; editing and revision of
spite the normal levels of total testosterone original draft have been performed by H.C.;
and estradiol (Aquila et al., 2009; Rittenberg S.B.; I.S.; V.N.P; and M.M.A-D. All authors
et al., 2011). Thus, it was concluded by re- have read and agreed to the published version
searchers that sperm motility and progressive of the manuscript.
motilityis correlated with serum levels of
25(OH)D. Vitamin D deficiency (<10 ng/ml) Conflict of interest
in males results in a lower proportion of mo- The authors declare no conflict of interest.
tile, progressive motile, and morphological-
lynormal spermatozoa (Jensen et al., 2011). Funding
To evaluate the positive role of vitamin D No funds, grants, or other support were re-
supplementation in men’s infertility, further ceived for this paper.
advanced investigations are highly antici-
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