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Reviewing the Evidence on Vitamin D Supplementation in the Management of

Testosterone Status and Its Effects on Male Reproductive System (Testis and
Prostate): Mechanistically Dazz...

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 Clinical Therapeutics/Volume xxx, Number xxx, xxxx

Reviewing the Evidence on Vitamin D

Supplementation in the Management of Testosterone
Status and Its Effects on Male Reproductive System
(Testis and Prostate): Mechanistically Dazzling but
Clinically Disappointing
Heitor O. Santos, RDa; Scott Howell, PhDb; Keith Nichols, MDb; and
Filipe J. Teixeira, RD, PhDc
a
School of Medicine, Federal University of Uberlandia, Uberlandia, Minas Gerais, Brazil;
b
Center for Research, Tier 1 Health and Wellness, Chattanooga, TN, USA; and cResearch
Center for Biosciences & Health Technologies, Universidade Lus
ofona de Humanidades e
Tecnologias, Lisboa, Portugal

ABSTRACT there is no apparent evidence to support the use of

vitamin D supplementation to increase testosterone
Purpose: Vitamin D supplementation has been
levels and to improve clinical outcomes related to the
suggested to increase testosterone levels. The primary
male reproductive system. (Clin Ther. xxxx;xxx:xxx)
purpose of this literature review was to critically
© 2020 Elsevier Inc.
assess the physiologic effects of vitamin D
Key words: male hypogonadism, 25(OH)D, testos-
supplementation on serum testosterone
terone, vitamin D.
concentrations in men and the secondary purpose
was to evaluate the feasibility of vitamin D status
toward urologic health (testis and prostate).
Methods: A structured literature review was INTRODUCTION
performed using the Cochrane, MEDLINE, and Web Vitamin D (VitD) deficiency, detected by low serum
of Science databases. The literature search 25-hydroxyvitamin D (25[OH]D), is considered a
encompassed studies published between 2011 and worldwide pandemic.1,2 Accordingly, observational
2019. data indicate that low 25(OH)D concentrations are
Findings: Observational studies suggest an associated with the prevalence of autoimmune
association between higher testosterone and serum diseases, cancers, sarcopenia, and dysregulation in
vitamin D concentrations. Conversely, most gut microbiota.3e8
randomized clinical trials that investigated the effect In addition to VitD deficiency, the prevalence of
of vitamin D administration on testosterone levels decreasing testosterone levels is also epidemiologically
have failed to detect any significant effect. related to senescence9 and daily endocrine disrupting
Physiologically, vitamin D is engaging in chemical exposure regardless of age.10e12 Fatigue, lack
spermatogenesis, but it remains unclear whether of energy, reduced strength, frailty, and decreased
vitamin D is a determinant of fertility. With prostate sexual performance are the main symptoms of low
support, the management of vitamin D status has testosterone levels.13 Indeed, testosterone management
been associated with a decreased prevalence of is essential for male health because lower levels are
benign prostatic hyperplasia and symptoms (ie, lower associated with an increased risk of all-cause and
urinary tract symptoms). However, with prostate
cancer, there is a paucity of evidence pertaining to
Accepted for publication March 24, 2020
vitamin D supplementation. https://doi.org/10.1016/j.clinthera.2020.03.016
Implications: Mechanistically, vitamin D exhibits 0149-2918/$ - see front matter
essential roles in the testis and prostate; otherwise, © 2020 Elsevier Inc.

▪▪▪ xxxx 1
 Clinical Therapeutics

cardiovascular mortality.14 Interestingly, the VitD insufficiency (30e50 nmol/L or 12e20 ng/mL),
receptor (VDR) is expressed not only in myocytes but deficiency (<30 nmol/L or <12 ng/mL), sufficiency
also in the male sex system, including prostate and (>50 nmol/L or >20 ng/mL), and toxicity
testis.15,16 (>250 nmol/L or >100 ng/mL with hypercalciuria
Despite the putative benefits of VitD and suppressed parathyroid hormone).19 The
supplementation on health (eg, as a cardiometabolic consensus for prevention of rickets and osteomalacia
support), VitD3 supplementation, even in with VitD supplementation recommends 400 IU/
considerable doses, recently failed to prevent type 2 d and at least 600 IU/d from birth to 12 months of
diabetes and cardiovascular disease in individuals at age and beyond 12 months of age, respectively.19 To
high risk for these diseases.17,18 However, there is no the best of our knowledge, however, there are no
discernable evidence regarding VitD supplementation specific recommendations for male hypogonadism.
for the management of male health, at least through Physicians and dietitians have appropriate roles for
an emphasis on the reproductive system. Therefore, prescribing supplementation of VitD. However,
our primary aim was to critically review the dietitians should be limited to a tolerable upper limit.
physiologic effects of VitD supplementation on serum The upper limit of VitD was 2000 IU/d in the past,20
testosterone concentrations, and our secondary aim but current guidelines expanded the upper limit to
was to assess the feasibility of VitD status to promote 10,000 IU/d for adult and elderly people, focusing on
urologic health in the areas of semen and prostate. the pleiotropic effects of supplementation.21

METHODS VitD and Testosterone Levels

A literature review was performed using Cochrane, Genotypes of the VitD receptor gene are associated
MEDLINE, and Web of Science databases with the
with serum sex hormone concentrations that have
goal of identifying relevant studies to describe and important clinical implications for testosterone.22 The
consolidate intervention data that analyzed the effects putative pathway between the active form of VitD,
of VitD supplementation on serum testosterone in known as calcitriol or 1,25-dihydroxyvitamin D3
humans. A detailed English-language literature search (1,25[OH]2D3), and its receptors is shown in Fig. 2.
was based on the following key words: Enzymatic actions are the presumed primary
cholecalciferol OR ergocalciferol OR vitamin D OR mechanisms that stimulate increases in testosterone
vitamin D2 OR vitamin D3 OR 25(OH)D OR 25- and dihydrotestosterone in men.
hydroxycholecalciferol OR 25-hydroxyvitamin D In evidence-based practice, both clinical trials and
AND FSH OR follicle-stimulating hormone OR free
observational studies deserve attention to characterize
testosterone OR LH OR luteinizing hormone OR sex the association between VitD status and testosterone
hormone-binding globulin OR SHBG OR levels in men. The sections below provide and detail
testosterone OR total testosterone. The literature the hierarchy of evidence from randomized controlled
search encompassed studies published between 2011 trials and broaden the scope of evidence with
and 2019. Fig. 1 shows the 2404 identified titles, observational studies.
yielding 192 potential abstracts, that were retrieved.
Subsequently, 8 full-length publications of clinical
trials that analyzed serum testosterone concentrations Clinical Trials
were included in the review. To expand the evidence Most intervention studies exerted no efficacy to
on urologic health, an additional search was increase total testosterone concentrations given the
performed with the same databases with no overall harmonized reference ranges (260e300 to
delimitation of study type or publication date. 850e920 ng/dL; 2.6e3 to 8.5e9.2 ng/mL; or 9e10.4
to 29.5e1.9 nmol/L).23 Collectively, the effects of
Definition of VitD Status: Serum Dosage and VitD supplementation on testosterone concentrations
Supplementation Doses in clinical trials are given in the Table I. Of all the
According to the Global Consensus studies, only a trial by Canguven et al24 used
Recommendations of the Endocrine Society, serum ergocalciferol (VitD2) supplementation. In this sense,
25(OH)D concentrations are classified as follows: the body of evidence assessing the more appropriate

2 Volume xxx Number xxx

 H.O. Santos et al.

Figure 1. Flow diagram of the included studies on serum testosterone levels.

VitD3 supplementation failed to produce clinically Analysis of data from the Longitudinal Aging Study
meaningful effects. Amsterdam of 643 Dutch men (aged
65 years) found
similar positive associations among 25(OH)D levels,
Observational Studies total testosterone levels, and bioavailable
Despite unsubstantiated support of VitD testosterone.36 On adjustment for covariates, men
supplementation as a testosterone-boosting agent, with serum 25(OH)D levels >75 nmol/L exhibited
there are strong linear associations between lower higher total testosterone levels than men with serum
serum levels of 25(OH)D and reduced serum 25(OH)D levels <25, 25 to 50, and 50e75 nmol/L.
testosterone, the latter of which may be low enough Interestingly, only the men with serum 25(OH)D
to meet current hypogonadism diagnosis criteria.24,25 levels >75 nmol/L had higher bioavailable
The deficiency of 25(OH)D is strongly associated testosterone compared with those with serum
with low serum testosterone levels in elderly men.34 25(OH)D levels <25 nmol/L. The association did not
A cohort study by Tak et al35 of 652 Korean men hold for any other serum 25(OH)D level comparison,
(mean age, 57 years) reported that 49% of the men and there was no association between lower serum
were 25(OH)D deficient and only 15% attained 25(OH)D levels and hypogonadism or
sufficient levels.35 In addition, men in the highest gonadotrophins.
quartile of serum 25(OH)D (26.51 ng/mL) exhibited In a cross-sectional study of 2299 elderly men,
higher total testosterone levels when compared with those with severe 25(OH)D deficiency and those
men in the lowest quartile (<15.28 ng/mL). with 25(OH)D sufficiency had 470 ng/dL and

▪▪▪ xxxx 3
 Clinical Therapeutics

Figure 2. The active form of vitamin D (VitD) increases the expression of androgen metabolism enzymes (ie,
P450scc and SRD5A1). 25-Hydroxyvitamin D3 (1,25[OH]2D3) binds to its membrane receptor and
consequently further binds to the nuclear receptor, forming the VitD receptor (VDR)eretinoid X
receptor (RXR) heterodimer. There are VitD-dependent genes in the nucleus, and when the VDR-RXR
heterodimer is activated, the vitamin D response element (VDRE) signals the expression of androgen
enzymes in the mitochondria. P450scc acts primarily on the hormone cascade, which is responsible
for converting cholesterol into pregnenolone. After pregnenolone is synthesized, several enzymatic
actions lead to testosterone formation, whose processes occur in the endoplasmic reticulum.
Increased expression of SRD5A1 by virtue of 1,25(OH)2D3 signaling enhances the conversion of
testosterone to dihydrotestosterone. The proposed pathway for the association between the active
form of VitD and increased testosterone levels in humans occurs in the Leydig cells, whereas the
association with increased levels of dihydrotestosterone occurs in cells that predominantly express
isoforms of 5a-reductase, one of which is SRD5A1. Some precursors of the testosterone pathway
should be investigated through randomized clinical trials for better clinical insight. DHEA,
dehydroepiandrosterone.

531 ng/dL of total testosterone, respectively.37 In A recent cross-sectional study found no statistically
another cross-sectional study, consisting of 1362 significant associations between 25(OH)D and
male participants, serum 25(OH)D was positively testosterone concentrations among Polish male ice
associated with total and free testosterone levels, hockey players.38 In context, the sample size was
indicating a linear association between 25(OH)D small (n ¼ 50), and the mean concentrations of
and total testosterone as well as 25(OH)D and free 25(OH)D and total testosterone were 30.3 ng/mL
testosterone at lower levels of 25(OH)D of and 19.2 nmol/L, respectively, whereas both values
approximately >75e85 nmol/L, while reaching a fell within their respective reference ranges.39,40 In
plateau at higher levels (>100 nmol/l).32 contrast, among 404 Polish elderly men, a significant

4 Volume xxx Number xxx

 H.O. Santos et al.

Table I. Effect of VitD administration on testosterone concentrations.

Source Study Population Study VitD Dose, IU Serum 25(OH)D Total Secondary
Design Pre / After Testosterone Endocrine
(Duration) [Difference], Outcome in Outcomes
nmol/L VitD
Intervention

Lerchbaum 94 Men with low RCT 20,000 per week 56 / 89 [33] 4 E2, LH, FSH,
et al,25 testosterone (12 wk) of VitD3 SBHG, free
2018 levels testosterone,
(12.7 nmol/L), and free
mean age of androgen index
47 y did not
change.
Saha 180 Young RCT
60,000 per week 22.5 / 85.9 Y2.1 for all SBHG and free
et al,26 healthy men (6 mo)
of VitD3 for [63.4] groups androgen index
2018 8 wk followed did not
by 60,000 change.
fortnightly for
4 mo
Zittermann 133 Patients with RCT 4000 per day of 36.5 / 63.9 4 SHBG levels did
et al,27 advanced heart (36 mo) VitD3 [27.4] not change
2018 failure, mean And free
total testosterone
testosterone and bioactive
level of testosterone
11.2 nmol/L, decreased
mean age of significantly in
55 y vitamin D and
placebo groups
Canguven 102 VitD- Prospective 600,000 per 37.2 / 121.2 [ 0.49 Increased erectile
et al,24 deficient study month of [84] function scores
2017 patients mean (12 mo) ergocalciferol; and decreased
total once serum E2 levels; LH
testosterone 25(OH)D concentrations
level of level reached did not change
12.46 nmol/L, 75 nmol/L,
mean of 53 y VitD dose was
switched to
600,000 every
2 mo
Lerchbaum 98 Healthy men, RCT 20,000 per week 52 / 107 [55] 4 E2, LH, FSH,
et al,28 mean (12 wk) of VitD3 SBHG, free
2017 testosterone testosterone,
level of and free
19.1 nmol/L, androgen index
mean age of did not change
39 y
(continued on next page)

▪▪▪ xxxx 5
Clinical Therapeutics

Table I. (Continued )
Source Study Population Study VitD Dose, IU Serum 25(OH)D Total Secondary
Design Pre / After Testosterone Endocrine
(Duration) [Difference], Outcome in Outcomes
nmol/L VitD
Intervention

Heijboer 92 Patients, RCT (6 wk) 2000 per day of 46.5 / 73.5 4 Not analyzed
et al,29 mean total VitD3 [27]
2015 testosterone
level of
15 nmol/L,
mean age of
63 y
49 VitD-deficient RCT 600 per day of 27 / 57 [30] 4
patients, mean (16 wk) VitD3
total
testosterone
level of
11 nmol/L,
mean age of
82 y
43 VitD-deficient RCT 1200 per day of 27.5 / 63.5 4
patients, mean (16 wk) VitD3 [36]
total
testosterone
level of
13 nmol/L,
mean age of
53 y
Jorde 282 Heathy men, RCT (6 20,000e40,000 48.2 / 70.6 4 Free testosterone,
et al,30 mean total e12 mo) per week of [22.4] LH, FSH, and
2013 testosterone VitD3 SHBG did not
level of change
14.3 nmol/L,
mean age of
51 y
Pilz et al,31 54 Healthy, RCT 3332 per day of 32.5 / 86.4 [2.7 Increased
2011 overweight (12 mo) VitD3 [53.9] bioactive
men, mean testosterone
total (5.21 from
testosterone 6.25 nmol/L)
level of and free
10.7 nmol/L, testosterone

6 Volume xxx Number xxx

 H.O. Santos et al.

Table I. (Continued )
Source Study Population Study VitD Dose, IU Serum 25(OH)D Total Secondary
Design Pre / After Testosterone Endocrine
(Duration) [Difference], Outcome in Outcomes
nmol/L VitD
Intervention

mean age of levels (from

49 y 0.222 to
0.267 nmol/L)

E2 ¼ estradiol; FSH ¼ follicle-stimulating hormone; LH ¼ luteinizing hormone; 25(OH)D ¼ 25-hydroxyvitamin D;

RCT ¼ randomized clinical trial; SBHG ¼ VitD ¼ vitamin D.

correlation among 25(OH)D levels, serum testosterone The cross-sectional Survey on Prevalence in East
level, and the free androgen index was found with China for Metabolic Diseases and Risk Factors
respect to different genotypes of VDR (SPECT-China) study of 2854 men, using a definition
polymorphisms, including heterozygous AG of hypogonadism as total testosterone level
(rs731236) and Ff (rs10735810) as well as <11.3 nmol/L or free testosterone level <22.56 pmol/L,
homozygous GG (rs7975232) and BB (rs1544410).41 reported strong associations between increased
Interestingly, a double cohort study examined the quartiles of 25(OH)D and decreased odds of
association between the VDR polymorphisms hypogonadism (P < .01).46 On a comparison of the
rs2228570 (Fok1) and rs731236 (Taql) and lowest quartile to the highest quartile of 25(OH)D in
luteinizing hormone (LH) levels in the context of an adjusted model, the association persisted (odds
supraphysiologic testosterone doses.42 At baseline, ratio ¼ 1.50; 95% CI, 1.14e1.97). Notably, a recent
healthy men homozygous for Fok1 (C-allele carriers) mendelian randomization analysis47 that assessed new
had 30% higher LH levels at baseline than data from the SPECT-China study replicated and
testosterone carriers before testosterone was confirmed the associations found by Wang et al.46 In
administered, thus providing some evidence to the analysis of 4254 Chinese men, lower 25(OH)D
support a biological mechanism among 25(OH)D levels were associated with lower total testosterone,
levels, LH values, and testosterone levels in those suggesting a biological effect on gonadal function and
with the Fok1 VDR polymorphism. the hypothalamicepituitaryegonadal axis. To date,
The clinical usefulness of VitD screening might however, randomized controlled trials have failed to
differ, depending on patient metabolic status and the find a causal effect (Table I).
diagnosis of male hypogonadism. Both 25(OH)D
deficiency and male hypogonadism significantly Semen Parameters
increase the risk of metabolic syndrome.33,43,44 In a VitD is metabolized in the testis where VDR-
study composed of 612 men, a correlation was regulated proteins and enzymes mediate VitD in
detected between 25(OH)D levels and testosterone human spermatozoa, increasing intracellular calcium
concentrations in individuals without metabolic concentrations and thus inducing sperm motility.15
syndrome. These men exhibited higher 25(OH)D The versatility of VitD as a signaling molecule in the
and testosterone levels when compared with men male reproductive organs provides systemic and local
with metabolic syndrome (14.43 vs 12.53 ng/mL for underpinnings for its interplay with both sperm and
25[OH]D and 532 vs 458 ng/dL for total testosterone metabolism. Mechanistically, testosterone
testosterone).45 is primarily important for the initiation and

▪▪▪ xxxx 7
 Clinical Therapeutics

maintenance of spermatogenesis,48 especially in is important to provide an accurate characterization

meiosis.49 of the interplay between the VitD status and sperm
In a recent cross-sectional study, a significant parameters. In this regard, Zhu et al55 found that
decrease in 25(OH)D levels in patients with altered oligospermia, asthenospermia, oligoasthenospermia,
sperm parameters (total count, motility, and and azoospermia were significantly lower with serum
morphology) was detected.50 Patients with normal 1,25(OH)2D3 but not 25(OH)D3 in infertile Chinese
sperm parameters (n ¼ 186) had 81 nmol/L of men (n ¼ 186) compared with fertile men (n ¼ 79).
25(OH)D, whereas those with altered sperm
parameters (n ¼ 127) had 65 nmol/L of 25(OH)D. Prostate Support
Moreover, serum testosterone levels were significantly Adequate 25(OH)D levels have produced promising
and positively correlated with 25(OH)D. Infertile results toward prostate volume and benign prostatic
patients with altered sperm parameters had 3.32 ng/ hyperplasia (BPH). Clinical attention is required,
mL of total testosterone, whereas fertile patients with especially when prostate volume is > 30 mL,56
normal sperm parameters exhibited 8.04 ng/mL. In whereas diagnosed BPH, a phenomenon due to the
turn, Tirabassi et al,51 through a retrospective excessive growth of both stromal and epithelial cells
analysis of 104 andrologic patients, with 25(OH)D of the prostate, is a more common form of lower
levels of 20.8 (lowest quartile) versus 40.8 ng/mL urinary tract symptoms (LUTS).57 In a cohort of 434
(highest quartile), had a positive association between men with LUTS, lower 25(OH)D levels were
total sperm motility and 25(OH)D values but not associated with higher total overactive bladder
between total and free testosterone levels.51 Other symptom scores, especially during the winter. In
studies found no associations between 25(OH)D patients with 25(OH)D deficiency, consenting to
concentrations and testosterone levels, further intramuscular VitD3 therapy administered as 200,000
indicating inconsistent data with regard to semen IU in a single dose, the total overactive bladder
parameters.52,53 Results of a cross-sectional study of symptom scores significantly decreased after 2
young healthy men (n ¼ 307), in which 8e62 nmol/L months of VitD replacement while increasing 25(OH)
and 94e227 nmol/L were considered as low and D levels from 13.7 to 25.3 ng/mL.58 In a prospective
high 25(OH)D levels, respectively, offered no caseecontrol study, patients with LUTS (n ¼ 70) had
evidence to suggest that 25(OH)D is a risk factor for lower 25(OH)D levels and a larger prostate
poor semen quality, testosterone, LH, follicle- compared with the control group (n ¼ 80). The mean
stimulating hormone (FSH), and inhibin levels.53 25(OH)D values were 41 vs 70 nmol/L, whereas
Likewise, the Copenhagen-Bone-Gonadal Study, mean prostate sizes were 50 and 31 g, respectively
which examined 1189 infertile men, reported that for cases (patients with LUTS) and controls.59 In a
neither total testosterone nor free T concentrations prospective, observational study, associations among
were altered between the lowest and the highest 25(OH)D deficiency, BPH, and LUTS in men with
quartiles of serum 25(OH)D (<25 vs >75 nmol/L), as type 2 diabetes mellitus were found. Individuals with
well as LH, sex hormoneebinding globulin, and prostate volume 30 mL (n ¼ 27) had a mean
inhibin values.52 Among sperm parameters, only 25(OH)D concentration of 44.8 nmol/L, whereas a
motility was elevated in the highest 25(OH)D quartile. mean of 29.2 nmol/L was detected for those with a
According to Hammoud et al,54 both high and low prostate volume
30 mL (n ¼ 40).60
levels of serum 25(OH)D can be negatively associated Along with VitD supplementation, analogues of
with semen parameters.54 In their study, men with VitD have emerged as appealing agents to decrease
concentrations between 20 and 50 ng/mL exhibited prostate volume in patients with BPH.57 In this
maximal values of semen parameters. Conversely, regard, a double-blinded, randomized, placebo-
those with 25(OH)D levels >50 ng/mL had lower controlled clinical trial of 119 patients with
percentages of normal sperm head, progressive motile diagnosed BPH and prostate volume
40 mL found
sperm, sperm concentration, and total progressive that prostate volume decreased 2.90 mL in the
motile sperm count, whereas men with 25(OH)D treatment group compared with a 4.32-mL increase
levels <20 ng/mL had lower total sperm count and in the placebo group after 12 weeks of treatment
total progressive motile sperm. Besides 25(OH)D, it with 125 mg/d of BXL628, a VitD analogue.61

8 Volume xxx Number xxx

 H.O. Santos et al.

Prostate and Testis Cancer germ cell testicular cancer, with 65%e85%
Taken together, the management of VitD status is a presenting with levels <30 ng/mL, 25%e36% with
feasible approach as a part of routine screening for levels <20 ng/mL, and 6%e18% with levels
male health, particularly being a biomarker with <10 ng/mL. In turn, the study by Schepisi et al70 of
applicability to mitigate the increased prevalence of unilateral testicular cancer noted that 11 patients of
BPH. However, with prostate cancer, the evidence is 58 patients (19%) had normal 25(OH)D values,
inconsistent throughout the wide spectrum of VitD. whereas 47 (81%) had suboptimal levels.70
For instance, in an observational study in which 571 Similarly, Foresta et al,71 investigating 125
men with elevated prostate-specific antigen levels or normotestosteronemic patients with testicular cancer
abnormal digital rectal examination findings were and unilateral orchiectomy, found that 25(OH)D
investigated, serum levels
30 mL were inversely levels were significantly lower in case patients
associated, especially in men with BPH, but not for compared with 41 age-matched healthy controls
prostate cancer.62 (41.6 vs 74.9 nmol/L). Interestingly, within the same
In 2012, Gilbert et al63 investigated 1447 patients study, hypogonadotropic hypogonadal patients after
with prostate cancer and 1449 healthy controls, 3 months of therapy with gonadotropins had
finding a 2-fold increased risk of advanced versus increased 25(OH)D levels from 38.2 to 58.9 nmol/L,
localized prostate cancer and high-grade versus low- suggesting an interplay between male gonadal health
grade cancer in men who were 25(OH)D deficient. and VitD status.
However, there was no evidence pertaining to an
association between total 25(OH)D and overall ViTD Supplementation Versus Nutraceutical
prostate cancer incidence. Moreover, the meta- Agents
analysis of Gilbert et al,64 which encompassed 25 We have previously reported that medicinal doses of
studies, found that neither an increase in serum levels zinc and some herbal medicines (eg, mucuna and
of 10 ng/mL of 25(OH)D and 10 pg/mL of ashwagandha) are appealing tools as a natural
1,25(OH)2D3 nor an increment increase of 1000 IU testosterone adjuvant in physiologic ranges.72,73 In
from VitD intake decreased prostate cancer risk. In the present review, VitD3 supplementation failed as a
addition, Layne et al65 did not find an association testosterone adjuvant when the whole body of
between 25(OH)D levels and overall prostate cancer evidence was taken into perspective. Taking into
among 226 patients with prostate cancer and 452 account the search of natural products on urologic
controls in black men.65 On the other hand, serum health, we also found that certain herbal medicines as
VitD-binding protein was significantly and inversely well as foodstuffs have some degree of effectiveness
associated with prostate cancer risk. More recently, a to manage noncancer prostate diseases.73 However,
nested caseecontrol study within the Melbourne VitD supplementation remains inconclusive to the
Collaborative Cohort Study examined the association extent of improving clinical assessment of prostate
between serum 25(OH)D and prostate cancer in 824 diseases. Given the paucity of evidence on VitD
middle-aged Australian case patients and 1648 supplementation and prostate health, instead of its
controls.66 In alignment with previous studies, serum use, widespread, healthy lifestyle changes based on
25(OH)D levels were not inversely associated with physical exercise and weight management are more
prostate cancer (hazard ratio ¼ 1.11; 95% CI, rational approaches.74,75
0.82e1.48).
Despite a high prostate cancer prevalence, Limitations and Clinical Aspects
testicular cancer is the most common cancer in adult Even with a systematic search strategy to find
men (ie, 20e30 years old),67 which is also a disease quality evidence, only 8 interventional studies were
of concern in older men.68 Nappi et al69 detected included in the present review to describe findings
reduced 25(OH)D levels among 82 patients with about the effects of VitD supplementation on

▪▪▪ xxxx 9
 Clinical Therapeutics

testosterone levels. Most studies examined young physiologic importance of VitD in modulating the
males and addressed a small number of middle-aged testicular steroidogenesis, there is no sound evidence
men with borderline adequate 25(OH)D levels. Thus for the use of VitD supplementation as a testosterone
far, the evidence based on this clinical background adjuvant, as detailed in this structured literature
with VitD3 supplementation points to a lack of review. The evidence on VitD supplementation
efficacy of VitD3 as a testosterone adjuvant, remains inconsistent in urologic conditions,
especially in eugonadal conditions. This global insight particularly as an adjuvant to improve sperm and
is important because lay consumers have a wide prostate parameters. Practitioners should refrain from
aspiration to increase testosterone levels using any enthusiasm regarding VitD supplementation and
nutraceutical agents that are vulnerable to 25(OH)D screening for urologic heath. The evidence
unsubstantiated advertising, which even extends to presented in this review represents another nail in the
clinical practice. coffin for VitD as a magic bullet. Definitive long-term
To the best of our knowledge, no clinical trials have clinical trials are needed to confirm the effects of
analyzed the interdependence between VitD VitD supplementation on diseases critical to urologic
supplementation in elderly mean with low health with an emphasis on hypogonadism, BPH, and
concentrations of 25(OH)D and testosterone. prostate cancer.
Therefore, further research with the particular aim to
assess this population with requisite measures is
worthwhile to provide key knowledge for
AUTHOR CONTRIBUTIONS
HOS wrote the manuscript and carried out the
endocrinologists, urologists, andrologists, and
conception and design of the article; FJT, KN, SH
dietitians. On top of that, systematic reviews with
wrote the manuscript.
meta-analyses are a reasonable means of propagating
pooled estimates and general findings, but the focus
on the clinical characteristics of patients should be CONFLICT OF INTEREST
extended to who would most need VitD The authors have indicated that they have no conflicts
supplementation. of interest regarding the content of this article.
Moreover, there is increasing evidence of resistance
to the achievement of adequate 25(OH)D
concentrations using conventional VitD ACKNOWLEDGMENTS
supplementation. For instance, because VitD is fat None.
soluble, accumulation is predominant in adipose
tissue.76 In this sense, obese individuals are more
susceptible to serum 25(OH)D deficiency when the REFERENCES
accumulation of VitD in the adipose tissue inhibits 1. Forrest KYZ, Stuhldreher WL. Prevalence and correlates of
release into systemic circulation, resulting in lower vitamin D deficiency in US adults. Nutr Res. 2011;31:
levels.77 Furthermore, very high doses of vitamin D 48e54. https://doi.org/10.1016/j.nutres.2010.12.001.
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Address correspondence to: Heitor O. Santos, RD, School of Medicine,

Federal University of Uberlandia, Av. Para, nº1720, 2U Block,
Umuarama Campus 38400-902, Uberlandia, MG, Brazil. E-mail:
[email protected]

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