Human Reproduction, Vol.27, No.10 pp.

3015–3027, 2012
Advanced Access publication on July 23, 2012 doi:10.1093/humrep/des248

REVIEW Reproductive biology

Relevance of vitamin D in reproduction

Janelle Luk 1, Saioa Torrealday 1, Genevieve Neal Perry 2,3,4, and
Lubna Pal 1,*
1
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology and Reproductive Sciences, 333 Cedar Street,
P.O. Box 208063, Yale University School of Medicine, New Haven, CT 06520, USA 2Department of Obstetrics and Gynecology and

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Women’s Health, NY, USA 3Dominick Purpura Department of Neuroscience, Albert Einstein College of Medicine, NY, USA 4Montefiore
Medical Center, Albert Einstein College of Medicine, NY, USA

*Correspondence address. Tel: +203-785-4016; Fax: +203-785-7134; E-mail: [email protected].

Submitted on December 10, 2011; resubmitted on May 25, 2012; accepted on May 31, 2012

abstract: The steroid hormone vitamin D is historically recognized for its relevance to bone health and calcium homeostasis. Recent
years have witnessed a shift in focus to non-skeletal benefits of vitamin D; in this latter context, an accruing body of literature attests to a
relevance of vitamin D to reproductive physiology. This article reviews the existing data about the diverse and previously underappreciated
roles for vitamin D in reproductive health. A large body of available literature suggests that vitamin D deficiency may be detrimental to re-
productive biology. However, given that our appreciation of vitamin D’s role in reproductive physiology is almost entirely shaped by ‘asso-
ciative’ studies and that data based on prospective interventional trials are limited, these concepts remain predominantly conjectural. Exact
mechanisms whereby vitamin D may participate in the regulation of reproductive physiology remain far from clear. This review underscores a
need for appropriately designed intervention trials to address the existing knowledge gaps and to delineate the specific roles of vitamin D
signaling in reproductive biology.

Key words: female tract / sperm quality / oocyte quality / environmental / effects

Introduction Physiology
A role for vitamin D in bone health was first reported in the 1920’s
Metabolism
when McCollum and colleagues created a rat model of diet-induced
rickets (Mellanby, 1919). Disease manifestations were found to be In humans, the predominant source of vitamin D is endogenous cuta-
prevented by a fat-soluble agent that was discovered in oxidized neous synthesis, whereas dietary sources contribute to ,20% of
cod liver oil, and was subsequently named vitamin D (Mellanby, the circulating levels of vitamin D (Holick et al., 1987; Lips, 2006).
1919; Rajakumar, 2003). Although the importance of this vitamin Endogenous synthesis of vitamin D (cholecalciferol or D3) occurs
in calcium-phosphate homeostasis and for bone health was estab- after photolytic conversion of 7-dehydrocholesterol, located in the
lished early on, an understanding of the molecular biology of dermal fibroblasts and epidermal keratinocytes, by the ultraviolet B
vitamin D was thwarted until the late 1960’s when DeLuca and col- component of sunlight (wavelength between 290 nm and 315 nm;
leagues (Lund and DeLuca, 1966) generated radio-labeled vitamin Ashwell et al., 2010; Fig. 1).
D, a critical step in allowing the recognition of nuclear localization Nutritional forms of vitamin D consist of D3 (cholecalciferol), which
of vitamin D in a variety of tissues (Rajakumar, 2003; Christakos is found in foods such as fatty fish (i.e. sardine, salmon and mackerel),
et al., 2007). A succession of strides in vitamin D research has eggs and calf liver, and D2 (ergocalciferol) which is manufactured
since furthered our understandings of the myriad roles that through the ultraviolet irradiation of ergosterol from yeast and fungi
vitamin D plays in biological responses. Non-skeletal effects of (i.e. mushrooms; Vieth, 1999; Moore et al., 2004). Both forms of
vitamin D have been the focus of much interest in the past dietary vitamin D are inactive and are efficiently absorbed by the
decade and an accruing body of literature is supportive of a rele- gut. The dietary vitamin D (D3 and D2) is nearly identical to the skin-
vance of vitamin D for a variety of organ systems beyond the skel- derived form of this seco steroid; in this review, the term vitamin D is
eton (Reichel et al., 1989; Walters, 1992). This review focuses on implied to reflect either of the two variants (D3 and D2).
data that are based on non-human animal models as well as clinical The circulating vitamin D prohormone (i.e. dietary or endogenously
studies and identify a relevance of an individual’s vitamin D status to synthesized) is further metabolized by a set of cytochrome P450
reproductive biology. enzymes; the hepatic 25-hydroxylase (CYP27A1), converts the

& The Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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3016 Luk et al.

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Figure 1 An overview of vitamin D metabolism and salient actions. VDBP, vitamin D binding protein; D2, ergocalciferol; D3, cholecalciferol.

prohormone to an intermediary metabolite, 25-hydroxy vitamin D et al., 2007), a ligand-activated transcription factor that belongs to the
(25(OH)D), whereas 1-a hydroxylase (CYP27B1), primarily from nuclear hormone receptor super-family. VDR is expressed in a variety
the kidneys, generates the metabolically active form, 1,25-di-hydroxy of tissues other than the skeleton, including the intestines, parathyroid
vitamin D (1,25(OH)2D; Schuster, 2011). The two circulating metabo- glands, immune cells, and more recently, the hypothalamic –pituitary
lites (i.e. 25(OH)D and 1,25(OH)2D) demonstrate distinct kinetics axis and the reproductive tract (Christakos et al., 2007; Mizwicki
and physiological potency. 25(OH)D has a half-life of 2– 3 weeks, and Norman, 2009). The presence of VDR in the ovary, uterus, pla-
and its circulating levels are recognized to reflect bodily stores of centa and the testis suggests a regulatory role for vitamin D in repro-
the vitamin. 1,25(OH)2D in contrast, has a much shorter half-life of ductive physiology (Weisman et al., 1979; Dokoh et al., 1983; Stumpf
4–6 h and represents the most biologically active variant of vitamin et al., 1987a; Johnson et al., 1996). The VDR binds 1,25(OH)2D with
D (Vieth, 1999). An overview of metabolism and salient actions of an affinity in the range of 0.1 –1 nM compared with .100 mM for
vitamin D are summarized in Fig. 1. the lesser active 25(OH)D metabolite (Wecksler and Norman,
Renal 1-a hydroxylase (CYP27B1) is recognized as the principal de- 1980a,b; Wecksler et al., 1980). The receptor-ligand binding initiates
terminant and the rate-limiting enzyme in the generation of the active a cascade of events that include receptor phosphorylation and
1,25(OH)2D metabolite. Recently, the expression of CYP27B1 has nuclear translocation; recruitment and heterodimerization with the
been described in a variety of non-renal tissues, suggesting the exist- 9-cis retinoid receptor (RXR) then ensues (Christakos et al., 1996).
ence of local mechanisms by which the metabolically active form of The VDR/RXR heterodimer complexes with the steroid receptor
the vitamin D is generated (Zehnder et al., 2001; Fischer et al., co-activators, VDR-interacting protein and co-regulatory proteins,
2009). The activity of CYP27B1 is directly regulated by the parathyroid before binding to the vitamin D responsive elements within the pro-
hormone (PTH; Lund and DeLuca, 1966; Schuster, 2011). More re- moter region of target genes, thereby allows the transcription regula-
cently, the activity of CYP27B1 has been shown to be inhibited by tion of tissue-specific genes (Christakos et al., 1996).
fibroblast growth factor 23 (FGF-23), a component of the previously Although the effect of active 1,25(OH)2D on target cells primarily
unrecognized hormonal bone–parathyroid –kidney axis that is itself reflects genomic activity, more recent data suggest an additional non-
modulated by PTH, 1,25(OH)2D and serum phosphorus levels (Bai genomic signaling mechanism via membrane associated rapid response
et al., 2004; Martin et al., 2012). steroid-binding receptor (MARRS, also known as Erp57/Grp58); such
a mechanism is suggested in a variety of tissues including the intestine,
Mechanism of action bone, parathyroid gland, liver, monocytes and the pancreatic beta cells
Vitamin D belongs to the family of steroid hormones. The cellular (Chatterjee, 2001; Erben et al., 2002; Christakos et al., 2007; Yu et al.,
effects of vitamin D and its metabolites are mediated primarily 2012). The function of the non-genomic signaling pathway, however, is
through the cognate intranuclear vitamin D receptor (VDR; Christakos less understood. Signaling via the VDR has additionally been linked to
Vitamin D in reproduction 3017

CYP19 (aromatase) gene expression, functionally linking vitamin D Lessons from animal models
with the family of reproductive steroid hormones (Kinuta et al.,
The majority of the experimental data defining a role for 1,25
2000; for review Christakos et al., 2003).
(OH)2D, the active metabolite of vitamin D, in reproduction are
either derived from diet-induced vitamin D-deficient rodent models
or from transgenic Vdr or Cyp27b1 null mice (Halloran and
DeLuca, 1979; Johnson and DeLuca, 2001; Sun et al., 2010; Dicken
Pandemic of vitamin D deficiency et al., 2012). The available evidence makes a strong case for the im-
The data collected by the National Health and Nutrition Examination portance of vitamin D for procreative success, while underscoring
Surveys within North America document a 4-fold increase in the the need for additional studies to allow a better understanding of
prevalence of vitamin D deficiency over the past 10 –15 years with the mechanistic relevance of vitamin D in reproduction.
as much as 36% of the USA population being affected (Nesby-O’Dell

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et al., 2002; Looker et al., 2008). Embedded within these data are the
alarming findings that populations with the greatest physiological needs Vitamin D and male reproductive physiology: animal models
for vitamin D, such as pregnant women, neonates, children and ado- The expression of Vdr on sperm and throughout the male testes, the
lescents are also at highest risk for vitamin D deficiency (McCullough, presence and activity of Cyp27b1 in the testes and the evidence of
2007; Alemzadeh et al., 2008; Kovacs, 2008). local synthesis of 1,25(OH)2D within the Sertoli and Leydig cells all
Suboptimal dietary vitamin D intake, increasing environmental pol- attest to a relevance of vitamin D in male reproduction (Stumpf
lution, a shift in lifestyle with consequent reduced sun exposure, a con- et al., 1987b; Osmundsen et al., 1989; Kwiecinski et al., 1989a). Per-
comitant increased use of sunscreen arising from concerns about the turbations in male behavior, spermatogenesis and fertility are
carcinogenic potential of sunlight are all recognized as contributors to described in the context of vitamin D deficiency (Kinuta et al.,
the near-pandemic of vitamin D insufficiency (Diehl and Chiu, 2010). 2000). Inseminating wild-type females with sperm collected from
An inverse relationship between serum 25(OH)D levels and body diet-induced vitamin D deficient male rats resulted in 65% fewer
mass index (BMI) is also well described (Bell et al., 1988; Liel et al., sperm deposited in the genital tract, and 73% fewer pregnancies in
1988). Although a ‘cause and effect’ paradigm to this relationship is vitamin D sufficient female rats (Osmundsen et al., 1989; Kwiecinski
unclear, obesity is recognized as an independent risk factor for hypo- et al., 1989a). Likewise, oligoasthenospermia, hypergonadotrophic
vitaminosis D (Wortsman et al., 2000); sequestration of the fat soluble hypogonadism and altered tissue expression of aromatase activity
vitamin within the adipose tissue is proposed as a mechanism to are described in the transgenic Vdras well as in the Cyp27b1 null
explain the lower circulating levels of 25(OH)D observed in the over- mice; these data suggest a regulatory role for vitamin D signaling in
weight and the obese (Liel et al., 1988; Wortsman et al., 2000). gonadal function. Of interest,the reproductive and gonadal pheno-
While increasing the prevalence of obesity may partly explain the types of transgenic estrogen receptor alpha and aromatase null mice
escalating trends in vitamin D insufficiency (Nesby-O’Dell et al., are similar to the Vdrnull male mutant (Eddy et al., 1996; Mahato
2002; Looker et al., 2008), the latter in turn may itself be contributory et al., 2000; Couse et al., 2001). These latter observations may
to the burgeoning pandemic of obesity (Foss, 2009). Secondary hy- suggest that theimpaired spermatogenesis and subfertility that are ap-
perparathyroidism that occurs consequent to hypovitaminosis Dis parent in Vdrnull male mice may partly be mediated through defects in
suggested to stimulate 1-a hydroxylase activity, contributing to a com- estrogen signaling, a hypothesis that merits detailed assessment.
pensatory elevation in 1,25(OH)2D levels (Arunabh et al., 2003). Others, however, maintain that hypocalcemia and hypophosphatemia
Recent in vitro experiments suggest that 1,25(OH)2D causes an in- resulting from vitamin D deficiency are the primary mechanisms that
crease in the intra-adipocyte calcium ion concentration, which in underlie the observed defects in spermatogenesis. Vitamin D defi-
turn can stimulate lipogenesis and inhibit lipolysis (Shi et al., 2001; ciency related hypocalcemia is hypothesized to compromise capacita-
Zemel, 2002). Obesity is hypothesized to be linked to abnormal as tion and acrosome reactions required for fertilization(Breitbart, 2002).
well as reduced leptin receptor signaling (for review, Gautron and Elm-
quist, 2011). Interestingly, studies in transgenic leptin deficient and
Table I Vitamin D and reproduction.
leptin receptor knockout mice suggest that leptin and its cognate re-
ceptor may also regulate renal CYP27b1 and 1,25 (OH)2D synthesis Parameter Experimental Human
(Matsunuma and Horiuchi, 2007). models studies
........................................................................................
Folliculogenesis + +
Spermatogenesis + +

Vitamin D and reproduction Steroidogenesis + 2

Implantation + +
The importance of vitamin D for the reproductive biology is supported Relevance in pregnancy + +
by several rodent studies; an appreciation that vitamin D signaling may
Relevance for progeny + +
be relevant for reproductive health in humans, however, is relatively
recent (Table I). The goal of this review is to summarize a relatively A comparison between experimental models and human studies with regard to
underappreciated body of literature that highlights the diverse physio- recognized target effects of vitamin D on specified reproductive parameters.
+Evidence for involvement; 2no evidence for involvement; +contradictory
logical roles for vitamin D and its metabolites in reproductive evidence.
physiology.
3018 Luk et al.

Consistent with this hypothesis high calcium-phosphorous diets rescue cell line) that were transfected with wild-type (WT) VDR cDNA
male fertility in Vdrtransgenic null mice and in male rats with expressing vector and anti-Mullerian hormone (AMH) reporter
diet-induced vitamin D deficiency (Uhland et al., 1992; Kinuta et al., plasmid; these observations suggest that the promoter for AMH has
2000; Johnson and DeLuca, 2001). a putative domain for the vitamin D response element (Malloy
et al., 2009). AMH, a member of the transforming growth factor
Vitamin D and female reproductive physiology: animal model (TGF–b) family, is produced by the ovarian granulosa cells and is
Similar to the observations invitamin D deficient males, several lines of recognized to regulate follicular recruitment and selection, as well as
evidence suggest that vitamin D deficiency disrupts female reproduct- inhibit the aromatase activity (Durlinger et al., 2002; Visser et al.,
ive physiology(Halloran and DeLuca, 1980; Kwiecinksi et al., 1989b; 2006). Given that vitamin D signaling can directly modulate ovarian
Panda et al., 200; Dicken et al., 2012). Nuclear localization of AMH expression, it is plausible that vitamin D deficiency in females
1,25(OH)2D and VDR are described in a variety of female reproduct- may disrupt ovarian physiology via altering AMH signaling.
ive organs including the hypothalamus, pituitary gland, uterus, oviduct, In contrast to the males, the ability of calcium to rescue female re-

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ovary, mammary gland and the placenta. Diet-induced vitamin D de- productive physiology and fertility in vitamin D deficient animal models
ficiency in female rats results in severely compromised fertility: a is far from consistent; different studies have reported complete, partial
45– 70% reduction in the probability of becoming pregnant, 67 – or no rescue (Johnson and DeLuca, 2002; Sun et al., 2010; Dicken
100% reduction in the number of viable pups and 0 –33% probability et al., 2012). While Johnson et al. have suggested that calcium supple-
of rearing normal sized and healthy litters are described in experimen- mentation in the VDR null mice rescued female fertility, the magnitude
tal models of vitamin D deficiency (Halloran and DeLuca, 1980; Kwie- of effect in the described model is difficult to interpret because the
cinksi et al., 1989b). control group (wild type litter mates) was fed a high calcium diet
While the exact mechanisms are far from understood, disrupted es- and both groups had equally small litter sizes (5.29 + 2.1 versus
trogen signaling is hypothesized to contribute to impaired reproduct- 3.5 + 1.3; n ¼ 4–7; Johnson and DeLuca, 2001).
ive physiology in vitamin D deficient females (Yoshizawa et al., 1997; VDR is expressed in the uterine endometrial cells as well as in the
Panda et al., 2001).Similar to the males, female Vdrnull mice also immune cells residing within the uterine endometrium (Evans et al.,
exhibit hypergonadotropic hypogonadism accompanied by reduced 2006). In addition to uterine hypoplasia, impaired bone formation
aromatase activity (Kinuta et al., 2000). While hypergonadotropic and skeletal compromise are also evident in the Vdr null mice (i.e.
hypogonadism is common to aromatase deficient as well as the trans- phenotypes consistent with hypoestrogenism). The uteri of the Vdr
genic Vdror Cyp27b1 nullfemale mice, the ovarian phenotypes for null mice are responsive to estrogen priming suggesting the uterine
these animal models are quite different. Ovarian morphology in the defect in the Vdr null is in part a consequence of hypogonadism
aromatase null females is characterized by large hemorrhagic cysts, (Zarnani et al., 2010). However, neither estradiol priming nor
suggestive of an ovulatory defect (Britt et al., 2000, 2001). In contrast, calcium supplementation suppressed gonadotrophins nor rescued
in the Vdras well as in Cyp27b1 transgenic null females, the ovaries are the reproductive phenotype in Vdr null females.
devoid of corpora lutea, exhibit hypertrophied interstitial cells, and Heterogeneity in the phenotypes of females with vitamin D defi-
early follicular development appears to be arrested (Panda et al, ciency caused by Vdr and Cyp27b1 gene deletion suggest that our
2001; Dicken et al., 2012). Hypergonadotropic hypogonadism is understanding of the regulatory role of vitamin D is not complete.
evident in the Vdr transgenic null females, suggesting gonadotrophin In addition to abnormal reproductive phenotypes, Vdr null mice
resistant (Kinuta et al., 2000). The transgenic Cyp27b1 null females exhibit early aging that is characterized by cognitive dysfunction and
in contrast are eugonadotropic and exhibit a robust ovarian response alopecia; these latter features are not apparent in the Cyp27b1 trans-
to exogenous gonadotrophins (Dicken et al., 2012). While these data genic null mice, nor in comparably aged, diet-induced vitamin D defi-
identify that neither ovarian failure nor gonadotrophin resistance cient rats (Lester et al., 1982). It is possible that the disruption of the
accounts for the abnormal reproductive phenotype of the Cyp27b1 Vdr gene and the resultant inability to form VDR/RXR heterodimers
females, some degree of hypothalamic –pituitary axis dysfunction is, results in physiological effects that are distinct from those specific to
however, suggested by the follicular response to exogenous gonado- vitamin D deficiency alone (Keisala et al., 2009).
trophins that is described in the Cyp27b1 null mice (Dicken et al., A recent study using the Cyp27b1 transgenic null females compared
2012). Contrary to Dicken et al., however, Sun et al., observed with WT littermates demonstrated that mice fed regular mouse chow
reduced numbers of oocytes retrieved from the oviducts in the (deficient of active vitamin D) for 3 months post-weaning exhibited
Cyp27b1 null mice compared with WT controls following ovulation irregular estrous cycles, reduced fertility and decreased pup survival
induction in 24–25-old mice (Sun et al., 2010). Differences in the that appeared to be rescued by calcium–phosphate diet supplemen-
age of experimental animals may account for the disparity in observa- tation (Sun et al., 2010). However, this study was limited because
tions reported in the latter two studies; Dicken et al., focused on the the authors did not study females weaned onto a truly vitamin
young adult animals, whereas Sun et al., superovulated females who D-deficient diet; instead the females were weaned onto a regular
most likely were developmentally peri-pubertal. Thus, it is possible chow diet which is fortified with the vitamin D prohormone. The sig-
that the pool of gonadotrophin responsive oocytes is reduced in the nificance of this latter point is that when circulating 25(OH)D levels
Cyp27b1 null peri-pubertal animals compared with the young adult are high, as occurs in the Cyp27b1 and Vdr null experimental
females (Sun et al., 2010; Dicken et al., 2012). models (Panda et al., 2004), the 25(OH)D itself can activate Vdr
In a recent study by Malloy et al., the authors provide novel implica- (Rowling et al., 2007). Thus, it is likely that calcium supplementation
tions of Vdr-mediated signaling for ovarian function. An up-regulation rescued the reproductive phenotype of these females because high
of the luciferase activity was observed in HeLA cells (cervical cancer circulating levels of 25(OH)D allowed the recovery of VDR signaling
Vitamin D in reproduction 3019

and consequently a less dramatic phenotype. Consistent with this hy- sperm annulus (Blomberg et al., 2012). In a study comparing the ex-
pothesis, Dicken et al., demonstrated that the estrous cycle irregularity pression of CYP24A1 in the ejaculated sperm from 77 subfertile
was not rescued in Cyp27b1 null females weaned onto a diet devoid and 50 healthy young men, the authors observed significantly
of vitamin D but supplemented with calcium (Dicken et al., 2012). reduced CYP24A1-expressing spermatozoa in the subfertile men
compared with the healthy group (1 versus 25%, P , 0.001).
Vitamin D, pregnancy, parturition and lactation: animal models CYP24A1 expression was further observed to positively correlate
The importance of vitamin D in embryo implantation is also suggested. with sperm concentration, motility and morphology (P , 0.004 for
HOXA 10 is a transcription factor that is recognized as being critical each parameter). The authors further noted that the presence of
for embryo-endometrial cross talk which initiates the process of im- .3% CYP24A1-positive spermatozoa distinguished the healthy men
plantation. Endometrial expression of HOXA10 is up-regulated by from the subfertile men with a sensitivity of 66.0%, a specificity of
vitamin D, thereby raising a possibility that vitamin D signaling contri- 77.9% and a positive predictive value of 98.3% (Blomberg et al.,
2012). To understand if vitamin D signaling was causative to the

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butes to successful embryo implantation and to immune tolerance
(Curtis Hewitt et al., 2002; Du et al., 2005). observed associations, these authors further conducted in vitro func-
Alterations in maternal feeding behavior, milk production and lacta- tional studies on sperm from an additional 40 men (22 young, 18 sub-
tion are described in vitamin D deficient and hypocalcemic post-partum fertile); exposure to 1,25(OH)2D increased intracellular calcium
females (dams). Reduced maternal feeding and milk production are concentration and improved motility in the sperm from healthy
evident in experimental models of vitamin D deficiency (Brommage young subjects, but failed to impact on sperm from the subfertile
and DeLuca, 1984b). Dams with diet-induced vitamin D deficiency, men (Blomberg et al., 2012). A recent review by the same group of
exhibit anorexia, abnormal maternal behavior and reduced milk produc- investigators offers a comprehensive coverage of the non-genomic
tion (Brommage and DeLuca, 1984a; Brommage et al., 1984). Poor ma- effect of vitamin D in human spermatozoa (Bloomberg et al.,
ternal nutrition and reduced milk production are hypothesized to 2012b).In a cross-sectional study of 307 men, Ramlau-Hansen et al.,
contribute to failure in the pups to thrive and survive under condi- however, failed to identify any clinical relevance of vitamin D deficiency
tions of maternal vitamin D deficiency (Brommage and DeLuca, on sperm parameters (Ramlau-Hansen et al., 2011).
1984b). Despite the above-summarized evidence linking maternal While the aforementioned data imply a role for vitamin D and
vitamin D deficiency to poor outcomes in the offspring, it is difficult VDRsignaling in spermatogenesis, sperm maturation and testicular
to ascertain if the poor neonatal outcomes reflect impaired vitamin endocrine function, additional studies are required to clearly define
D signaling, calcium – phosphate dysregulation, or if the sequelae the importance of VDR signaling in male gamete and gonadal
were consequent to maternal malnutrition and/or reduced maternal physiology.
capacity to lactate.
As currently understood, while reproductive compromise is clearly
Vitamin D and female reproductive physiology: human data
evident in the animal models of vitamin D deficiency, the exact down- Several recent studies explore the role of vitamin D and its metabo-
stream mechanisms whereby reproductive physiology is affected is lites in overall health and in specific reproductive disorders of
minimally understood. women. VDR mRNA and protein are detected in the human endo-
metrium, myometrium, ovarian, cervical and breast tissues (Friedrich
Vitamin D and reproduction: relevance in et al., 2003; Vienonen et al., 2004). Vitamin D deficiency is hypothe-
sized to contribute to the pathophysiology of a spectrum of gyneco-
humans
logical disorders, of which polycystic ovary syndrome (PCOS)
As discussed in the preceding section, ample solid evidence exists sup- appears to be most well studied.
porting a role for vitamin D in the regulation of reproductive physi- A small number ofobservational studies identify an inverse associ-
ology in the non-human models. In contrast, literature describing a ation between serum 25(OH)D levels with insulin resistance, features
role for vitamin D in the reproductive biology of humans is, of hyperandrogenism and circulating androgens in women with PCOS
however, sparse and almost entirely correlative. (Panidis et al., 2005; Hahn et al., 2006; Mahmoudi et al., 2010; Ngo
et al., 2011; Wehr and Pilz). In an observational study, Thys-Jacobs
Vitamin D and male reproductive physiology: human data et al. describednormalization of menstrual cyclicity in 7 out of 9 oligo-
Calcium is recognized as a critical intracellular signal in male physiology menorrheic women with PCOS who underwent supplementation with
with defined roles during spermatogenesis, sperm motility, hyperacti- vitamin D and calcium over a 6 month period; the authors implied
vation and acrosome reaction (Yoshida et al., 2008). VDR is detected therapeutic efficacy of vitamin D for women with PCOS (Thys-Jacobs
in the human testis, prostate and in human spermatozoa (Corbett et al., 1999). Others report dietary supplementation with vitamin D or
et al., 2006). More recently, vitamin D metabolizing enzymes are an analog improves insulin sensitivity (Kotsa et al., 2009; Selimoglu
described in the human testis, the ejaculatory tract, mature spermato- et al., 2010), circulating testosterone (Selimoglu et al., 2010) and para-
zoa and in Leydig cells (Blomberg et al., 2012; Foresta et al., 2010). meters of ovarian folliculogenesis and ovulation (Rashidi et al., 2009).In
CYP24A1 is a vitamin D-metabolizing enzyme that acts as a check a pilot study of 12 overweight and vitamin D deficient women with
on vitamin D signaling; 24-hydroxylation is generally the first step in PCOS, we observed a significant lowering in circulating androgens
the catabolism of active metabolites of vitamin D. CYP24A1 is (total testosterone and androstenedione) following three month inter-
induced by 1,25(OH)2D, and offers a feedback mechanism to avoid vention with vitamin D and calcium (Pal et al., 2012).
vitamin D toxicity and to titrate cellular responsiveness to vitamin Insulin resistance, obesity, inflammation and dyslipidemia, i.e. meta-
D. CYP24A1 expression has recently been described in the human bolic phenomenon that are commonly encountered in PCOS, are well
3020 Luk et al.

described in the setting of vitamin D insufficiency (Botella-Carretero IVF, Ozkan et al.assessed 25(OH)D levels in the ovarian follicular fluid
et al., 2007; Holick, 2007; Foss, 2009);vitamin D insufficiency is thus and determined an association between vitamin D status and cycle
theorized to underlie the pathophysiology of PCOS. However, outcome. Follicular fluid levels of 25(OH)D were observed to be sig-
because the majority of women with PCOS are either overweight nificantly higher in women achieving clinical pregnancy following fresh
or obese it is difficult to determine if vitamin D deficiency independent embryo transfer compared with those with failed outcome (34.42 +
of excess body mass contributes to the pathogenesis of PCOS. 15.58 versus 25.62 + 10.53 ng/ml, P ¼ 0.013). Highest implantation
A limited number of studies relate vitamin D deficiency to premen- rates were observed in women with a follicular fluid level of
strual syndrome, uterine fibroids, dysmenorrhea and more recently to 25(OH)D in the highest tertile (43.01 + 10.65 ng/ml) compared
early menarche (Bertone-Johnson et al., 2010; Sharan et al., 2011; Vil- with those with follicular fluid 25(OH)D levels in the lower tertiles
lamor et al., 2011; Lasco et al., 2012). Compared with placeboa signifi- (P ¼ 0.041). While these data relate vitamin D status with reproduct-
cant improvement in severity of dysmenorrhea was observed over a ive success in otherwise healthy, albeit infertile, women undergoing
two month period following a single dose of 300 000 IU vitamin D; IVF (Ozkan et al., 2010), others fail to confirm these associations

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this latter study is one of the few instances where a cause-effect rela- (Aleyasin et al., 2011). Additionally another group of investigators
tionship between low vitamin D status and the studied outcome is reported adverse impact of higher 25(OH)D levels on embryo
supported by the randomized controlled study design (Lasco et al., quality (Anifandis et al., 2010). Additional studies are needed to
2012). explore these associations better and to study the direct effects of
A variety of reproductive tract tissues express VDR and messenger vitamin D and its metabolites on the endometrium and implantation.
RNA for 1CYP27B1. Expression of VDR is reported in normal and
neoplastic cervical (Friedrich et al., 2003), ovarian and breast tissue Vitamin D and pregnancy: human data
(Friedrich, 2000). While the role of vitamin D signaling incervical Maternal calcium metabolism undergoes dramatic modulation so as to
and ovarian cancer isunclear, a significant body of epidemiological maintain the skeletal mineralization needs of the developing fetus
data suggest vitamin D deficiency is a risk for non-inherited forms of (Abrams, 2007). The gravid woman’s physiology adapts to the escal-
breast cancer (Shao et al., 2012). Interestingly endometriosis has the ating fetal requirements with advancing gestation; increasing gastro-
distinction of being one of the few disorders identified as resulting intestinal calcium absorption is evident early in pregnancy, and
from arelative excess of vitamin D (Somigliana et al., 2007). A maximized in the last trimester (Cross et al., 1995; Ritchie et al.,
recent study on proteomic analysis of serum collected from patients 1998). The increasing fetal demand for calcium is further met by the
with endometriosisdemonstrated a significantly higher expression of increased production of 1,25(OH)2D via the maternal kidneys and pla-
vitamin D-binding protein (VDBP) in sera of patients with endometri- centa (Ritchie et al., 1998). Compared with pre-pregnancy levels,
osis (Faserl et al., 2011). Others have similarly demonstrated a there is a 2-fold increase in both the total plasma levels of
increased plasma and peritoneal fluid VDBP levels in patients with 1,25(OH)2D and VDBP in the first and second trimesters. In the
endometriosis compared with controls (Ferrero et al., 2005).An over- third trimester, however, a continued rise in 1,25(OH)2D occurs
expression of VDR and vitamin D metabolizing enzymes is also without a concomitant increase in VDBP, resulting in increased
described in the peritoneal lesions and in endometrial tissue of levels of free (unbound) 1,25(OH)2D (Urrutia and Thorp, 2012). Pla-
women with endometriosis compared with healthy controls (Agic cental hormones including parathyroid hormone-related protein
et al., 2007). The authors suggest that activity of immune cells and (PTHrP) and placental lactogen may be particularly relevant in modu-
cytokines that are thought to play pathogenic roles in the development lating vitamin D homeostasis during pregnancy (Hosking, 1996;
and maintenance of endometriosis may be modulated by the higher Kovacs, 2012). PTHrP, placental lactogen, as well as prolactin stimu-
than normal peritoneal levels of vitamin D and its metabolites (Agic late renal CYP27B1 activity, contributing to the increased circulating
et al., 2007). While these data imply that VDBP and vitamin D signaling levels of 1,25(OH)2D in pregnancy (Hosking, 1996; Kovacs,
may play a role in the pathogenesis of endometriosis, the underlying 2012).The significance of vitamin D for maternal and fetal wellbeing
mechanisms are minimally investigated. It is notable that existing is thus suggested by the aforementioned phenomena that ensure an
data describing abnormalities in vitamin D metabolism and levels in increased availability of the active form of vitamin D to the mother
disorders of reproductive tract are almost entirely associative; a and the fetus during pregnancy, particularly in the third trimester
direct cause and effect of the observed relationship requires (Urrutia and Thorp, 2012).
substantiation. Several pregnancy-related disorders that have been hypothesized to
Beyond the suggested associations with specific metabolicdisorders relate to maternal vitamin D deficiency includ pre-eclampsia, gesta-
a roleforvitamin D is also implied for procreative success in women. tional diabetes mellitus (GDM) and a risk for delivery by Cesarean
Serum 25(OH)D levels are reported to predict ovarian response in section (Fischer et al., 2007; Merewood et al., 2009; Shand et al.,
women undergoing ovulation induction with clomiphene citrate (CC). 2010; Soheilykhah et al., 2010). Pre-eclampsia is one of the most
Low levels of 25(OH)D and vitamin D deficiency (,25 nmol/l or common obstetric complications, and a significant contributor to ma-
,10 ng/ml) were found to be associated with lower rates of folliclede- ternal and fetal morbidity and mortality. While the etiology is not en-
velopment and pregnancy after ovarian stimulation with 50 mg CC (Ott tirely clear, abnormal placentation, poor placental perfusions,
et al., 2012); of note, the threshold taken to define vitamin D insuffi- endothelial dysfunction and oxidative stress are recognized mechan-
ciency in this latter study is consistent with a state of severe vitamin isms underlying pre-eclampsia. The presence of vitamin D and its
D deficiency (Hollis et al., 2011). Implications of vitamin D status for re- receptors in the placenta as well as the ability of vitamin D to modu-
productive success have also been suggested in women undergoing in late immune, inflammatory and vascular responses has suggested a
vitro fertilization (IVF). In a prospective study of 84 women undergoing causative role of maternal vitamin D deficiency in the pathogenesis
Vitamin D in reproduction 3021

of pre-eclampsia (Bodnar et al., 2007a). Higher maternal vitamin D with opportunistic illnesses (French et al., 2011; Mehta et al, 2011).
levels are associated with a lower incidence of pre-eclampsia and In a case–control study of 117 pregnant women diagnosed with
with lower blood pressure readings (Shand et al., 2010; Ringrose moderate-to-severe periodontal disease at ,26 weeks of gestation
et al., 2011). Others have explored the relationship between maternal compared with 118 periodontally healthy controls, Boggess et al. iden-
D levels earlier in pregnancy with the likelihood of developing pre- tified a 2-fold increase in the prevalence of vitamin D insufficiency
eclampsia during the course of pregnancy. A Norwegian study of (serum 25(OH)D , 75 nmol/l [i.e. ,30 ng/ml]) in women with peri-
.23 000 nulliparous pregnant women found that supplemental odontal disease (Boggess et al., 2011). Cause-specific mortality attrib-
vitamin D intake protects against the development of pre-eclampsia utable to HIV, disease progression and disease-related anemia were
(Haugen et al., 2009). The effects of maternal vitamin D supplementa- significantly higher in a cohort of HIV-positive gravid Tanzanian
tion on lowering blood pressures in the third trimester are reported in women with low vitamin D levels (serum 25(OH)D , 32 ng/ml)
a randomized control trial of vitamin D supplementation versus compared with those with normal vitamin D levels (Findelstein
control (Marya et al., 1987). In this study, 400 gravid women were ran- et al., 2011; Mehta et al., 2011). In a randomized, double-blind,

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domly selected to either receive calcium (375 mg/day) and vitamin D placebo-controlled trial by Mehta et al., 884 Tanzanian HIV-infected
(1200 IU/day) at 20–24 weeks onward or non-supplemented gravid women received either vitamin supplementation (including
throughout the pregnancy. At 32 and 36 weeks of pregnancy, the sys- vitamin D) or placebo. Women with low 25(OH)D levels (,32 ng/
tolic and diastolic blood pressure of the vitamin D supplementation ml) had significantly higher upper respiratory infections [odds ratio
group was significantly lower than the non-supplemented group. (OR): 1.27 (1.04– 1.54)], and thrush [OR: 2.74 (1.29– 5.83)] diag-
However, the incidence of pre-eclampsia in the supplemented group nosed during the first 2 years of follow-up (Mehta et al., 2011). Add-
(6%) was not significantly different from the non-supplemented itionally, women with low vitamin D status were at higher risk for
group (9%; Marya et al., 1987). The existing literature relating maternal HIV-related wasting (Mehta et al., 2011). The relationship between
vitamin D status with the risk of pre-eclampsia is equivocal. In a case – BV and vitamin D status has been explored in a study of .3500
control study, Yu et al. (2012) quantified maternal serum vitamin D women (pregnant and non-pregnant; Hensel et al., 2011); vitamin D
level in the first trimester and explored its relevance for risk of devel- deficiency (serum 25(OH)D , 30 ng/ml) was identified as an inde-
oping early (,34 weeks) or late (≥34 weeks) pre-eclampsia. The pendent determinant of risk for BV (OR: 2.9, 95% CI: 1.1–7.3) in
authors failed to identify any relationship between maternal serum the pregnant populations. Similarly, Bodnar et al. showed in a pro-
vitamin D levels with biochemical (pregnancy-associated plasma spective cohort study of 469 pregnancy women in the first trimester
protein) or biophysical (uterine artery pulsatility index and mean that the mean serum 25(OH)D concentration was lower among BV
arterial pressure) markers of impaired placental perfusion or function cases (29.5 nmol/l) compared with women with normal vaginal
(Yu et al., 2012). flora (40.1 nmol/l; Bodner et al., 2009). Approximately 57% of
Although a relationship between vitamin D deficiency and risk for women with a low serum 25(OH)D level (,20 nmol/l) had BV com-
type 2 diabetes mellitus is well described in non-pregnant populations pared with 23% of women with normal serum 25(OH)D levels
(Chiu et al., 2004), the association of vitamin D with GDM, however, (.80 nmol/l; Bodner et al., 2009). These two studies clearly show
has shown mixed results. In one case–control study by Zhang et al., an association between vitamin D deficiency and BV in pregnant
women with vitamin D deficiency early in pregnancy had a 2.66-fold women.
(confidence interval (CI): 1.01 –7.02) increased chance of developing As evident, the existing literature relating maternal status of vitamin
GDM compared with women with normal levels (Zhang et al., D with pregnancy-related outcomes is almost exclusively ‘associative’.
2008). Two additional case–control studies, however, failed to iden- While the data suggest that insufficient maternal levels of vitamin D
tify any relationship between maternal vitamin D levels and subse- may increase the likelihood of common obstetric conditions such as
quent maternal risk for GDM (Baker et al., 2012; Makgoba et al., pre-eclampsia, GDM and infectious entities such as BV, these concepts
2011). require additional investigation. If maternal vitamin D deficiency mod-
Maternal rickets and concomitant pelvic deformities are a recog- ulates maternal risk for the afore-discussed morbidities, aggressive
nized contributor to inefficient labor and difficulties with parturition. vitamin D supplementation in pregnancy would offer a simple, inex-
A recent study of 253 women identified a 4-fold increase in likelihood pensive and safe strategy that could hold the potential to positively
for delivery by Cesarean section in women with low vitamin D impact maternal and neonatal health. Additional studies are needed
(,37.5 nmol/l) at the time of delivery compared with those with to bridge gaps in knowledge regarding mechanism and the ability to
higher (.37.5 nmol/l) vitamin D levels (Merewood et al., 2009). rescue the pathophysiology with dietary vitamin D supplementation.
The increased risk of Cesarean section (emergent or elective) was
attributed to negative effects of low vitamin D levels on uterine mus- Maternal Vitamin D status and implications for fetal development
culature and contractibility. However, the relationship between and neonatal well-being: human data
vitamin D and the route of delivery is not consistent. Moreover, Maternal and cord blood levels of 25(OH)D have been shown to
others researchers fail to observe any effect of maternal vitamin D closely correlate across populations (Bassir et al., 2001; Wang et al.,
status (assessed early or mid-pregnancy or at the time of delivery) 2010; Dror et al., 2011; Hossain et al., 2011). Given the fetal depend-
on the route of delivery (Dror et al., 2011; Savvidou et al., 2012). ence on maternal stores of 25(OH)D freely crossing the placental
Maternal vitamin D deficiency has been linked to a predisposition to barrier, maternal vitamin D deficiency is likely to affect the fetus and
a spectrum of infectious etiologies including periodontal disease the health of the newborn.
(Boggess et al., 2011), bacterial vaginosis (BV; Bodner et al., 2009; Maternal vitamin D status may hold long-term implications for the
Hensel et al., 2011) and HIV morbidity and mortality associated health of the progeny. Recently, a prospective cohort study of 424
3022 Luk et al.

pregnant women demonstrated that maternal vitamin D insufficiency requires 4000 –6000 IU/day to transfer enough vitamin D into her
may affect fetal femoral bone development as early as 19 weeks of milk if she chooses not to give a vitamin D supplement to the infant
gestation (Mahon et al., 2010); lower maternal 25(OH)D concentra- (Hollis and Wagner, 2004; Endocrine Society Clinical Guidelines,
tions relate to greater femoral bone metaphyseal cross-sectional 2011).
area and higher femoral splaying index in the fetuses. Additionally a
longitudinal cohort study, Javaid et al., observed that lower maternal
25(OH)D serum levels correlated with a lower whole-body and Recommended daily vitamin D
lumbar spine bone mineral content in children at the age of 9 years intake
(Javaid et al., 2006).
Small randomized clinical trials and observational studies also Despite circulating 25(OH)D level being recognized to reliably reflect
suggest a relationship between higher maternal vitamin D levels in an individual’s vitamin D status, a consensus regarding the optimal
the third trimester of pregnancy with neonatal birthweight (Ertl serum level for health maintenance is, however, lacking (Aloia,

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et al., 2012). A reduced risk for small for gestational age (weight 2011). The revised guidelines issued by the Institute of Medicine
less than 10 percentile, Gairdner standards) babies was observed in (IOM) identify serum 25(OH)D threshold of 20 ng/ml (50 nmol/l),
59 women randomized to vitamin D supplementation (1000 IU D3 at and above which, adverse skeletal sequelae may be avoided
daily) initiated in the third trimester, compared with 67 gravid (IOM, 2011; ACOG, 2011; Table II). The Endocrine Society of
women given placebo. Nearly twice as many infants in the control North America, however, maintains a higher 25(OH)D threshold of
group were small for gestational age compared with those women re- 30 ng/ml to differentiate between states of vitamin D sufficiency
ceiving vitamin D supplementation (29 versus 15%; Brooke et al., (.30 ng/ml) and insufficiency (≤30 ng/ml ≥20 ng/ml). Of particular
1980). Higher birthweights were similarly observed in another rando- concern is whether the IOM specified RDA for vitamin D is sufficient
mized control study of vitamin D supplementation (a bolus each of to maintain 25(OH)D levels .30 ng/ml in the at-risk populations such
600 000 IU administered at gestational months 7 and 8, plus as those already deficient in vitamin D or during pregnancy and lacta-
1200 IU D2/day during the third trimester) versus placebo (Marya tion (Lee et al., 2007; IOM, 2011; Holick et al., 2012). The Endocrine
et al., 1987). More recently, Hollis et al. (2011) conducted the Society Clinical Practice Guidelines recommend higher daily allowance
largest randomized trial of nearly 500 pregnant women who were ran- for vitamin D during pregnancy and lactation than proposed by the
domized to supplementation with 400, 2000 or 4000 IU of vitamin D. IOM (Table III).
Although a significant improvement in circulating 25(OH)D levels was
seen across all groups, the investigators did not observe any differ-
ences in birthweights across the dose categories (Hollis et al., 2011).
Conclusions
Higher maternal serum levels of 25(OH)D have been related to a In the recent years emerging data have suggested that vitamin D is not
reduced likelihood of reactive airway disease in the children. Litonjua only critical for the maintenance of bone health and for calcium and
(2012) observed a 40% increased risk of asthma in children at ages of phosphate homeostasis, but also imposes multisystem regulatory
3–5 years whose mothers had low levels of 25(OH)D in pregnancy. effects that modulate overall wellbeing and health (Holick et al.,
Although childhood eczema, respiratory infections, neurocognitive 2007). Herein, we have reviewed the existing literature that supports
parameters and autism have all been related to maternal deficiency, a plausible role for vitamin D in reproductive physiology. Summarizing
a cause and effect relationship is not clear (Gale et al., 2008; Grant the available data, we have attempted to convey the similarities as well
and Soles, 2009; Morales et al., 2012; Whitehouse et al., 2012). Col- as differences in data collected from studies carried out in rats, trans-
lectively, the existing data imply that maternal vitamin D status may genic mice as well as in clinical settings. It is, however, noteworthy that
have long-lasting health implications for their progeny, and negative
connotations of maternal vitamin D deficiency may extend well into
the years beyond infancy. These concepts, yet again, underscore the Table II Recommended daily allowance and tolerable
need for appropriately designed future studies. upper limit for vitamin D as per guidelines issued by the
IOM.
Vitamin D and lactation: human data
Human breast milk is a poor source of vitamin D (Hollis and Wagner, Age RDA vitamin D Upper limit vitamin D
(years) (IU/day) (IU/day)
2011; Holick et al., 2012). Therefore, maternal vitamin D sufficiency is ........................................................................................
thus particularly relevant in exclusively breastfed infants. Daily intake of 1– 3 600 2500
600 IU of vitamin D as per current recommendations (ACOG Com- 4– 8 600 3000
mittee Opinion, 2011; IOM, 2011) is suggested to be inadequate 9– 18 600 4000
for either prevention or for the correction of documented vitamin 19–50 600 4000
D deficiency during the periods of pregnancy and lactation (Hollis
51–70 600 4000
and Wagner, 2004; Bodnar et al., 2007b). Additional supplementation
71+ 800 4000
with 1000 IU of vitamin D beyond the dose inclusive in the commonly
Pregnancy 600 4000
utilized prenatal vitamins (400 IU) has been suggested to ensure that
serum levels of 25(OH)D are maintained .30 ng/ml (Endocrine Lactation 600 4000
Society Clinical Guidelines, 2011; Holick et al., 2011). To satisfy the Source: IOM (2011).
requirements of an infant who is exclusively breastfed, the mother
Vitamin D in reproduction 3023

D 1 alpha-hydroxylase, vitamin D 24-hydroxylase, and vitamin D

Table III Recommended daily allowance and tolerable 25-hydroxylase in endometriosis and gynecologic cancers. Reprod Sci
upper limit for vitamin D in pregnancy and lactation as 2007;14:486 – 497.
per the Endocrine Society Practice Guidelines. Alemzadeh R, Kichler J, Babar G, Calhoun M. Hypovitaminosis D in obese
children and adolescents: relationship with adiposity, insulin sensitivity,
Age Daily requirement Upper limit vitamin D ethnicity, and season. Metabolism 2008;57:183 – 191.
(IU/day) (IU/day)
........................................................................................ Aleyasin A, Hosseini MA, Mahdavi A, Safdarian L, Fallahi P, Mohajeri MR
Pregnancy et al. Predictive value of the level of vitamin D in follicular fluid on the
outcome of assisted reproductive technology. Eur J Obstet Gynecol
14–18 600– 1000 4000
Reprod Biol 2011;159:132 – 137.
19–30 1500–2000 10000 Aloia JF. Clinical review: the 2011 report on dietary reference intake for
31–50 1500–2000 10000 vitamin D: where do we go from here? J Clin Endocrinol Metab 2011;
Lactation 10:2987– 2996.

Downloaded from https://academic.oup.com/humrep/article-abstract/27/10/3015/747482 by guest on 22 May 2019

14–18 600– 1000 4000 Anifandis GM, Dafopoulos K, Messini CI, Chalvatzas N, Liakos N,
Pournaras S et al. Prognostic value of follicular fluid 25-OH vitamin D
19–30 1500–2000 10000
and glucose levels in the IVF outcome. Reprod Biol Endocrinol 2010;
31–50 1500–2000 10000
8:91. Reprod Biol Endocrinol 2010 Jul 28; 8:91.
Source: Holick et al. (2011). Arunabh S, Pollack S, Yeh J, Aloia JF. Body fat content and
25-hydroxyvitamin D levels in healthy women. J Clin Endocrinol Metab
2003;88:157 – 161.
Ashwell M, Stone EM, Stolte H, Cashman KD, Macdonald H,
transgenic models of vitamin D deficiency (Vdr and cyp27b1 null) are
Lanham-New S, Hiom S, Webb A, Fraser D. UK Food Standards
not defined by a critical circulating level of vitamin D or its metabolites.
Agency Workshop Report: an investigation of the relative
Thus, the direct extrapolation of existing data from transgenic mice to contributions of diet and sunlight to vitamin D status. Br J Nutr 2010;
humans must be treated with caution. Nevertheless, a growing body 104:603– 611.
of literature suggests that an individual’s vitamin D status may adversely Bai X, Miao D, Li J, Goltzman D, Karaplis AC. Transgenic mice
impact reproductive functions. However, the dearth of prospective inter- overexpressing human fibroblast growth factor 23 (R176Q) delineate
ventional studies and studies that define the mechanisms whereby a putative role for parathyroid hormone in renal phosphate wasting
vitamin D affects reproductive physiology underscores the dire need disorders. Endocrinology 2004;145:5269 – 5279.
for appropriately designed intervention trials. Given its recognized Baker Am, Haeri S, Camargo CA Jr, Stuebe AM, Boggess KA. First
safety, accessibility and ease of administration vitamin D supplementation trimester maternal vitamin D status and risk for gestational diabetes
mellitus: a nested case – control study. Diabetes Metab Res Rev 2012;
could prove to be a cost effective strategy to improve public health.
28:164– 168.
Bassir M, Laborie S, Lapillonne A, Claris O, Chappuis MC, Salle BL.
Author’s’ roles Vitamin D deficiency in Iranian mothers and their neonates: a pilot
study. Acta Paediatr 2001;90:577– 579.
All authors contributed to the different components of the review Bell NH, Epstein S, Greene A, Shary J, Oexmann MJ, Shaw S. Evidence for
paper. All authors have drafted and/or critically read and revised alteration of the vitamin D-endocrine system in obese subjects. J Clin
the manuscript for important intellectual content and have approved Invest 1988;76:370 – 373.
the final version of the manuscript for submission. Bertone-Johnson ER, Chocano-Bedoya PO, Zagarins SE, Micka AE,
Ronnenberg AG. Dietary vitamin D intake, 25-hydroxyvitamin D3
levels and premenstrual syndrome in a college-aged population.
Funding J Steroid Biochem Mol Biol 2010;121:434 – 437.
Blomberg Jensen M, Jørgensen A, Nielsen JE, Bjerrum PJ, Skalkam M,
N.P.’s effort was supported by the R21 HD066355 and the Albert Ein- Petersen JH, Egeberg DL, Bangsbøll S, Andersen AN,
stein College of Medicine Department of Obstetrics and Gynecology Skakkebaek NE et al. Expression of the vitamin D metabolizing
and Women’s Health. enzyme CYP24A1 at the annulus of human spermatozoa may serve
as a novel marker of semen quality. Int J Androl 2012 [Epub ahead
of print].
Conflict of interest Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM.
Maternal vitamin D deficiency increases the risk of preeclampsia. J Clin
None declared. Endocrinol Metab 2007a;92:3517– 3522.
Bodnar LM, Simhan HN, Powers RW, Frank MP, Cooperstein E,
Roberts JM. High prevalence of vitamin D insufficiency in black and
References white pregnant women residing in the northern United States and
Abrams SA. In utero physiology: role in nutrient delivery and fetal their neonates. J Nutr 2007b;137:447 – 452.
development for calcium, phosphorus, and vitamin D. Am J Clin Nutr Bodner LM, Krohn MA, Sihan HN. Maternal vitamin D deficiency is
2007;85:604S – 607S. associated with bacterial vaginosis in the first trimester of pregnancy.
ACOG Committee Opinion. Vitamin D: screening and supplementation J Nutr 2009;139:1157– 1161.
during pregnancy. Obstet Gynecol 2011;118:197 – 198. Boggess K, Espinola J, Moss K, Bck J, Offenbacher S, Carmargo C. Vitamin
Agic A, Xu H, Altgassen C, Noack F, Wolfler MM, Diedrich K, Friedrich M D status and peridontal disease among pregnant women. J Periodontol
et al. Relative expression of 1,25-dihydroxyvitamin D3 receptor, vitamin 2011;82:195 – 200.
3024 Luk et al.

Botella-Carretero JI, Alvarez-Blasco F, Villafruela JJ, Balsa JA, Vázquez C, Dror DK, King JC, Durand DJ, Allen LH. Association of modifiable and
Escobar-Morreale HF. Vitamin D deficiency is associated with nonmodifiable factors with vitamin D status in pregnant women and
the metabolic syndrome in morbid obesity. Clin Nutr 2007; neonates in Oakland, CA. J Am Diet Assoc 2011;111:111 – 116.
26:573 – 580. Du H, Daftary GS, Lalwani SI, Taylor HS. Direct regulation of HOXA10 by
Breitbart H. Intracellular calcium regulation in sperm capacitation and 1,25-(OH)2D3 in human myelomonocytic cells and human endometrial
acrosomal reaction. Mol Cell Endocrinol 2002;187:139 – 144. stromal cells. Mol Endocrinol 2005;19:2222 – 2233.
Britt KL, Drummond AE, Cox VA, Dyson M, Wreford NG, Jones ME Durlinger AL, Visser JA, Themmen AP. Regulation of ovarian function: the
et al. An age-related ovarian phenotype in mice with targeted role of anti-Mullerian hormone. Reproduction 2002;124:601 – 609.
disruption of the Cyp 19 (aromatase) gene. Endocrinology 2000; Eddy EM, Washburn TF, Bunch DO, Goulding EH, Gladen BC,
141:2614 – 2623. Lubahn DB, Korach KS. Targeted disruption of the estrogen receptor
Britt KL, Drummond AE, Dyson M, Wreford NG, Jones ME, Simpson ER gene in male mice causes alteration of spermatogenesis and infertility.
et al. The ovarian phenotype of the aromatase knockout (ArKO) Endocrinology 1996;137:4796– 4805.
mouse. J Steroid Biochem Mol Biol 2001;79:181– 185. Endocrine Society Clinical Guidelines. Evaluation, treatment, and

Downloaded from https://academic.oup.com/humrep/article-abstract/27/10/3015/747482 by guest on 22 May 2019

Brommage R, DeLuca HF. Vitamin D-deficient rats produce reduced prevention of vitamin D deficiency: an Endocrine Society Clinical
quantities of a nutritionally adequate milk. Am J Physiol 1984a; Practice Guidelines. J Clin Endocrinol Metab 2011;96:1911 – 1930.
246:E221– E226. Erben RG, Soegiarto DW, Weber K, Zeitz U, Lieberherr M, Gniadecki R,
Brommage R, DeLuca HF. A maternal defect is responsible for growth Möller G, Adamski J, Balling R. Deletion of deoxyribonucleic acid binding
failure in vitamin D-deficient rat pups. Am J Physiol 1984b; domain of the vitamin D receptor abrogates genomic and nongenomic
246:E216– E220. functions of vitamin D. Mol Endocrinol 2002;16:1524– 1537.
Brommage R, Jarnagin K, DeLuca HF. 1,25-Dihydroxyvitamin D3 Ertl R, Yu Ck, Samaha R, Akolekar R, Nicolaides K. Maternal serum
normalizes maternal food consumption and pup growth in rats. Am J vitamin D at 11 – 13 weeks in pregnancies delivering small for
Physiol 1984;246:E227– E231. gestational age neonates. Fetal Diagn Ther 2012;31:103 – 108.
Brooke OG, Brown IR, Bone CD, Carter ND, Cleeve HJ, Maxwell JD, Evans KN, Nguyen L, Chan J, Innes BA, Bulmer JN, Kilby MD et al. Effects
Robinson VP, Winder SM. Vitamin D supplementation in pregnant of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 on cytokine
Asian women: effects on calcium status and fetal growth. Br Med J production by human decidual cells. Biol Reprod 2006;75:816 – 822.
1980;280:751 – 754. Faserl K, Golderer G, Kremser L, Lindner H, Sarg B, Wildt L et al.
Chatterjee M. Vitamin D and genomic stability. Mutat Res 2001; Polymorphism in vitamin D-binding protein as a genetic risk factor in
475:69– 87. the pathogenesis of endometriosis. J Clin Endocrinol Metab 2011;
Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with 96:E233 –E241.
insulin resistance and beta cell dysfunction. Am J Clin Nutr 2004; Ferrero S, Gillott DJ, Anserini P, Remorgida V, Price KM, Ragni N,
79:820 – 825. Grudzinskas JG. Vitamin D binding protein in endometriosis. J Soc
Christakos S, Raval-Pandya M, Wernyj RP, Yang W. Genomic mechanisms Gynecol Investig. 2005;12:272– 277.
involved in the pleiotropic actions of 1,25-dihydroxyvitamin D3. Biochem Findelstein JL, Mehta S, Duggan CP, Spiegelman S, Aboud S, Kupka R,
J 1996;316:361 – 371. Msamanga GI, Fawzi WW. Predictors of anaemia and iron deficiency
Christakos S, Barletta F, Huening M, Dhawan P, Liu Y, Porta A, Peng X. in HIV-infected pregnant women in Tanzania: a potential role for
Vitamin D target proteins: function and regulation. J Cell Biochem vitamin D and parasitic infections. Public Health Nutr 2011;15:928– 937.
2003;88:238 – 244. Fischer D, Schroer A, Lüdders D, Cordes T, Bücker B, Reichrath J,
Christakos S, Dhawan P, Benn B, Porta A, Hediger M, Oh GT, Jeung EB, Friedrich M. Metabolism of vitamin D3 in the placental tissue of
Zhong Y, Ajibade D, Dhawan K, Joshi S. Vitamin D: molecular normal and preeclampsia complicated pregnancies and premature
mechanism of action. Ann N Y Acad Sci 2007;1116:340– 348. births. Clin Exp Obstet Gynecol 2007;34:80 – 84.
Corbett ST, Hill O, Nangia AK. Vitamin D receptor found in human Fischer D, Thome M, Becker S, Cordes T, Diedrich K, Friedrich M, Thill M.
sperm. Urology 2006;68:1345 – 1349. Expression of 25-hydroxyvitamin D3-24-hydroxylase in benign and
Couse JE, Mahato D, Eddy EM, Korach KS. Molecular mechanism of malignant ovarian cell lines and tissue. Anticancer Res 2009;
estrogen action in the male: insights from the estrogen receptor null 29:3635 – 3639.
mice. Reprod Fertil Dev 2001;13:211 – 219. Foresta C, Selice R, Di Mambro A, Strapazzon G. Testiculopathy and
Cross NA, Hillman LS, Allen SH, Krause GF, Vieira NE. Calcium vitamin D insufficiency. Lancet 2010;376:1301.
homeostasis and bone metabolism during pregnancy, lactation, Foss YJ. Vitamin D deficiency is the cause of common obesity. Med
and postweaning: a longitudinal study. Am J Clin Nutr 1995;61: Hypotheses 2009;72:314 – 321.
514 – 523. French AL, Adeyemi OM, Agniel DM, Evans CT, Yin MT, Anastos K. The
Curtis Hewitt S, Goulding EH, Eddy EM, Korach KS. Studies using the association of HIV status with bacterial vaginosis and vitamin D in the
estrogen receptor alpha knockout uterus demonstrate that United States. J Women’s Health 2011;20:1497 – 1503.
implantation but not decidualization-associated signaling is estrogen Friedrich M. Vitamin D and breast cancer: new approaches for hormonal
dependent. Biol Reprod 2002;67:1268 – 1277. therapy of breast cancer. Clin Exp Obstet Gynecol 2000;27:77 – 82.
Dicken CL, Israel D, Davis JB, Sun Y, Shu J, Hardin J, Neal-Perry G. Friedrich M, Rafi L, Mitschele T, Tilgen W, Schmidt W, Reichrath J.
Peripubertal vitamin D3 deficiency delays puberty and disrupts the Analysis of the vitamin D system in cervical carcinomas, breast cancer
estrous cycle in adult female mice. Biol Reprod, 2012 [Epub ahead of and ovarian cancer. Recent Results Cancer Res 2003;164:239 – 246.
print]. Gale CR, Robinson SM, Harvy NC, Javaid MK, Jiang B, Martyn CN,
Diehl JW, Chiu MW. Effects of ambient sunlight and photoprotection on Godfrey KM, Cooper C, Princess Anne Hospital Study Group.
vitamin D status. Dermatol Ther 2010;23:48 – 60. Maternal vitamin D status during pregnancy and child outcomes. Eur J
Dokoh S, Donaldson CA, Marion SL, Pike JW, Haussler MR. The ovary: a Clin Nutr 2008;62:68– 77.
target organ for 1,25-dihydroxyvitamin D3. Endocrinology 1983; Gautron L, Elmquist JK. Sixteen years and counting: an update on leptin in
112:200– 206. energy balance. J Clin Invest 2011;121:2087 – 2093.
Vitamin D in reproduction 3025

Grant WB, Soles CM. Epidemiologic evidence supporting the role of Keisala T, Minasyan A, Lou YR, Zou J, Kalueff AV, Pyykkö I, Tuohimaa P.
maternal vitamin D deficiency as a risk factor for the development of Premature aging in vitamin D receptor mutant mice. J Steroid Biochem
infantile autism. Dermatoendocrinology 2009;1:223 –228. Mol Biol 2009;115:91 –97.
Hahn S, Haselhorst U, Tan S, Quadbeck B, Schmidt M, Roesler S, Kinuta K, Tanaka H, Moriwake T, Aya K, Kato S, Seino Y. Vitamin D is an
Kimmig R, Mann K, Janssen OE. Low serum 25-hydroxyvitamin D important factor in estrogen biosynthesis of both female and male
concentrations are associated with insulin resistance and obesity in gonads. Endocrinology 2000;141:1317 – 1324.
women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes Kotsa K, Yavropoulou MP, Anastasiou O, Yovos JG. Role of vitamin D
2006;114:577 – 583. treatment in glucose metabolism in polycystic ovary syndrome. Fertil
Halloran BP, DeLuca HF. Vitamin D deficiency and reproduction in rats. Steril 2009;92:1053– 1058.
Science 1979;204:73 – 74. Kovacs CS. Vitamin D in pregnancy and lactation: maternal, fetal, and
Halloran BP, DeLuca HF. Effect of vitamin D deficiency on fertility and neonatal outcomes from human and animal studies. Am J Clin Nutr
reproductive capacity in the female rat. J Nutr 1980;110:1573 – 1580. 2008;88:520S – 528S.
Haugen M, Brantsaeter AL, Trogstad L, Alexander J, Roth C, Magnus P, Kovacs CS. The role of vitamin D in pregnancy and lactation: insights from

Downloaded from https://academic.oup.com/humrep/article-abstract/27/10/3015/747482 by guest on 22 May 2019

Meltzer HM. Vitamin D supplementation and reduced risk of animal models and clinical studies. Annu Rev Nutr 2012 [Epub ahead of
preeclampsia in nulliparous women. Epidemiology 2009;20:720 – 726. print].
Hensel KJ, Randis TM, Gelber SE, Ratner AJ. Pregnancy-specific association Kwiecinski GG, Petrie GI, DeLuca HF. Vitamin D is necessary for
of vitamin D deficiency and bacterial vaginosis. Am J Obstet Gynecol 2011; reproductive functions of the male rat. J Nutr 1989a;119:741 – 744.
204:41.e1– 41.e9. Kwiecinksi GG, Petrie GI, DeLuca HF. 1,25-Dihydroxyvitamin D3 restores
Holick MF. Vitamin D deficiency: review. N Engl J Med 2007;357:266– 281. fertility of vitamin D-deficient female rats. Am J Physiol 1989b;
Holick MF, Smith E, Pincus S. Skin as the site of vitamin D synthesis and 256:E483– E487.
target tissue for 1,25-dihydroxyvitamin D3. Use of calcitriol Lasco A, Catalano A, Benvenga S. Improvement of primary dysmenorrhea
(1,25-dihydroxyvitamin D3) for treatment of psoriasis. Arch Dermatol caused by a single oral dose of vitamin D: results of a randomized,
1987;123:1677 – 1683. double-blind, placebo-controlled study. Arch Intern Med 2012;
Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, 172:366– 367.
Heaney RP, Murad MH, Weaver CM, Endocrine Society. Evaluation, Lee JM, Smith JR, Philipp BL, Chen TC, Mathieu J, Holick MF. Vitamin D
treatment, and prevention of vitamin D deficiency: an Endocrine deficiency in a healthy group of mothers and newborn infants. Clin
Society Clinical Practice Guideline. J Clin Endocrinol Metab 2011; Pediatr (Phila) 2007;46:42 – 44.
7:1911 – 1930. Lester GE, VanderWiel CJ, Gray TK, Talmage RV. Vitamin D deficiency in
Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, rats with normal serum calcium concentrations. Proc Natl Acad Sci 1982;
Heaney RP, Murad MH, Weaver CM. Guidelines for preventing and 79:4791– 4794.
treating vitamin D deficiency and insufficiency revisited. J Clin Liel Y, Ulmer E, Shary J, Hollis BW, Bell NH. Low circulating vitamin D in
Endocrinol Metab 2012;97:1153 – 1158. obesity. Calcif Tissue Int 1988;43:199– 201.
Hollis BW, Wagner CL. Vitamin D requirements during lactation: Lips P. Vitamin D physiology. Prog Biophys Mol Biol 2006;92:4 –8.
high-dose maternal supplementation as therapy to prevent Litonjua AA. Vitamin D deficiency as a risk factor for childhood
hypovitaminosis D for both the mother and the nursing infant. Am J allergic disease and asthma. Curr Opin Allergy Clin Immunol 2012;
Clin Nutr 2004;80:1752S– 1758S. 12:179– 185.
Hollis BW, Wagner CL. The vitamin D requirement during human Looker AC, Pfeiffer CM, Lacher DA, Schleicher RL, Picciano MF,
lactation: the facts and IOM’s ‘utter’ failure. Public Health Nutr 2011; Yetley EA. Serum 25-hydroxyvitamin D status of the US population:
14:748– 749. 1988 – 1994 compared with 2000 – 2004. Am J Clin Nutr 2008;
Hollis BW, Honson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D 88:1519– 1527.
supplementation during pregnancy: double-blind, randomized clinical Lund J, DeLuca HF. Biologically active metabolite of vitamin D3 from bone,
trial of safety and effectiveness. J Bone Miner Res 2011;26:2341 – 2357. liver, and blood serum. J Lipid Res 1966;6:739 – 744.
Hosking DJ. Calcium homeostasis in pregnancy. Clin Endocrinol 1996; Mahato D, Goulding EH, Korach KS, Eddy EM. Spermatogenic cells do not
45:1– 6. require estrogen receptor-alpha for development or function.
Hossain N, Khanani R, Hussain-Kanani F, Shah T, Arif S, Pal L. High Endocrinology 2000;141:1273 – 1276.
prevalence of vitamin D deficiency in Pakistani mothers and their Mahmoudi T, Gourabi H, Ashrafi M, Yazdi RS, Ezabadi Z. Calciotropic
newborns. Int J Gynaecol Obstet 2011;12:229 –233. hormones, insulin resistance, and the polycystic ovary syndrome. Fertil
IOM (Institute of Medicine). Dietary Reference Intakes for Calcium and Steril 2010;93:1208– 1214.
Vitamin D. Committee to Review Dietary Reference Intakes for Calcium Mahon P, Harvey N, Crozier S, Inskip H, Robinson S, Arden N,
and Vitamin D. Washington, DC: National Academies Press, Institute Swaminathan R, Cooper C, Godfrey K, SWS Study Group. Low
of Medicine, 2011. maternal vitamin D status and fetal bone development: cohort study.
Javaid MK, Crozier SR, Harvey NC, Gale CR, Dennison EM, Boucher BJ. J Bone Miner Res 2010;25:14 – 19.
Maternal vitamin D status during pregnancy and childhood bone mass Makgoba M, Nelson SM, Savvidou M, Messow CM, Nicolaides K, Satter N.
at age 9 years: a longitudinal study. Lancet 2006;367:36 – 43. First-trimester circulating 25-hydroxyvitamin D levels and
Johnson LE, DeLuca HF. Vitamin D receptor null mutant mice fed high development of gestational diabetes mellitus. Diabetes Care 2011;
levels of calcium are fertile. J Nutr 2001;131:1787– 1791. 34:1091– 1093.
Johnson LE, DeLuca HF. Reproductive defects are corrected in vitamin Malloy PJ, Peng L, Wang J, Feldman D. Interaction of the vitamin D
D-deficient female rats fed a high calcium, phosphorus and lactose receptor with a vitamin D response element in the Mullerian-inhibiting
diet. J Nutr 2002;132:2270 – 2273. substance (MIS) promoter: regulation of MIS expression by calcitriol in
Johnson JA, Grande JP, Roche PC, Kumar R. Immunohistochemical prostate cancer cells. Endocrinology 2009;150:1580– 1587.
detection and distribution of the 1,25-dihydroxyvitamin D3 receptor Martin A, David V, Quarles LD. Regulation and function of the FGF23/
in rat reproductive tissues. Histochem Cell Biol 1996;105:7 –15. Klotho endocrine pathways. Physiol Rev 2012;92:131 – 155.
3026 Luk et al.

Marya RK, Rathee S, Manrow M. Effect of calcium and vitamin D effects of calcium and vitamin D on skeletal and mineral homeostasis.
supplementation on toxaemia of pregnancy. Gynecol Obstet Invest J Biol Chem 2004;279:16754 – 16766.
1987;24:38 – 42. Panidis D, Balaris C, Farmakiotis D, Rousso D, Kourtis A, Balaris V,
Matsunuma A, Horiuchi N. Leptin attenuates gene expression for Katsikis I, Zournatzi V, Diamanti-Kandarakis E. Serum parathyroid
renal 25-hydroxyvitamin D3-1alpha-hydroxylase in mice via the hormone concentrations are increased in women with polycystic
long form of the leptin receptor. Arch Biochem Biophys 2007; ovary syndrome. Clin Chem 2005;51:1691 – 1697.
463:118– 127. Rajakumar K. Vitamin D, cod-liver oil, sunlight, and rickets: a historical
McCullough ML. Vitamin D deficiency in pregnancy: bringing the issues to perspective. Pediatrics 2003;112:e132 – e135.
light. J Nutr 2007;137:305 – 306. Ramlau-Hansen CH, Moeller UK, Bonde JP, Olsen J, Thulstrup AM. Are
Mehta S, Mugusi F, Spiegelman D, Villamor E, Finkelstein JL, Hertzmark E, serum levels of vitamin D associated with semen quality? Results from
Giovannucci EL, Msamanga GI, Fawzi WW. Vitamin D status and its a cross-sectional study in young healthy men. Fertil Steril 2011;
association with morbidity including wasting and opportunistic illnesses 95:1000 – 1004.
in HIV-infected women in Tanzania. AIDS Patient Care STDs 2011; Rashidi B, Haghollahi F, Shariat M, Zayerii F. The effects of calcium-vitamin

Downloaded from https://academic.oup.com/humrep/article-abstract/27/10/3015/747482 by guest on 22 May 2019

25:579 – 585. D and metformin on polycystic ovary syndrome: a pilot study. Taiwan J
Mellanby E. An experimental investigation of rickets. Lancet 1919; Obstet Gynecol 2009;48:142– 147.
1:407 – 412. Reichel H, Koeffler HP, Norman AW. The role of vitamin D endocrine
Merewood A, Mehta SD, Chen TC, Bauchner H, Holick MF. Association system in health and disease. N Engl J Med 1989;320:980 – 991.
between severe vitamin D deficiency and primary caesarean section. Ringrose JS, Paul-Jenssen AM, Wilson M, Blanco L, Ward H, Wilson TN.
J Clin Endocrinol Metab 2009;94:940 – 945. Vitamin D and hypertension in pregnancy. Clin Invest Med 2011;
Mizwicki MT, Norman AW. The vitamin D sterol-vitamin D receptor 34:E147 –E154.
ensemble model offers unique insights into both genomic and Ritchie LD, Fung EB, Halloran BP, Turnlund JR, Van Loan MD, Cann CE,
rapid-response signaling. Sci Signal 2009;2:re4. King JC. A longitudinal study of calcium homeostasis during human
Moore C, Murphy MM, Keast DR, Holick MF. Vitamin D intake in the pregnancy and lactation and after resumption of menses. Am J Clin Nutr
United States. J Am Diet Assoc 2004;104:980 – 983. 1998;67:693–701.
Morales E, Romieu I, Guerra S, Ballester F, Rebagliato M, Vioque J, Rowling MJ, Gliniak C, Welsh J, Fleet JC. High dietary vitamin D prevents
Tardón A, Rodriguez Delhi C, Arranz L, Torrent M, Espada M, hypocalcemia and osteomalacia in CYP27B1 knockout mice. J Nutr
Basterrechea M, Sunyer J, INMA Project. Maternal vitamin D status in 2007;137:2608 – 2615.
pregnancy and risk of lower tract infections, wheeze and asthma in Savvidou M, Makgoba M, Castro P, Akolekar R, Nicolaies K. First trimester
offspring. Epidemiology 2012;23:64– 71. maternal serum vitamin D and mode of delivery. Br J Nutr 2012;24:1 – 4.
Nesby-O’Dell S, Scanlon KS, Cogswell ME, Gillespie C, Hollis BW, Schuster I. Cytochromes P450 are essential players in the vitamin D
Looker AC, Allen C et al. Hypovitaminosis D prevalence and signaling system. Biochim Biophys Acta 2011;1814:186– 199.
determinants among African American and white women of Selimoglu H, Duran C, Kiyici S, Ersoy C, Guclu M, Ozkaya G, Tuncel E,
reproductive age: third National Health and Nutrition Examination Erturk E, Imamoglu S. The effect of vitamin D replacement therapy
Survey, 1988– 1994. Am J Clin Nutr 2002;76:187– 192. on insulin resistance and androgen levels in women with polycystic
Ngo DT, Chan WP, Rajendran S, Heresztyn T, Amarasekera A, ovary syndrome. J Endocrinol Invest 2010;33:234 – 238.
Sverdlov AL, O’Loughlin PD, Morris HA, Chirkov YY, Norman RJ, Shand AW, Nassar N, Von Dadelszen P, Innis SM, Green TJ. Maternal
Horowitz JD. Determinants of insulin responsiveness in young vitamin D status in pregnancy and adverse pregnancy outcomes in a
women: impact of polycystic ovarian syndrome, nitric oxide, and group at high risk for pre-eclampsia. BJOG 2010;117:1593– 1598.
vitamin D. Nitric Oxide 2011;25:326 – 330. Shao T, Klein P, Grossbard ML. Vitamin D and breast cancer. Oncologist
Osmundsen BC, Huang HF, Anderson MB, Christakos S, Walters MR. 2012;17:36 – 45.
Multiple sites of action of the vitamin D endocrine system: FSH Sharan C, Halder SK, Thota C, Jaleel T, Nair S, Al-Hendy A. Vitamin D
stimulation of testis 1,25-dihydroxyvitamin D3 receptors. J Steroid inhibits proliferation of human uterine leiomyoma cells via
Biochem 1989;34:339– 343. catechol-O-methyltransferase. Fertil Steril 2011;95:247 – 253.
Ott J, Wattar L, Kurz C, Seemann R, Huber JC, Mayerhofer K, Vytiska- Shi H, Norman AW, Okamura WH, Sen A, Zemel MB.
Binstorfer E. Parameters for calcium metabolism in women with 1,25-Dihydroxyvitamin D3 modulates human adipocyte metabolism
polycystic ovary syndrome who undergo clomiphene citrate via nongenomic action. FASEB J 2001;15:2751– 2753.
stimulation: a prospective cohort study. Eur J Endocrinol 2012 [Epub Soheilykhah S, Mojibian M, Rashidi M, Rahimi-Saghand S, Jafari F. Maternal
ahead of print]. vitamin D status in gestational diabetes mellitus. Nutr Clin Pract 2010;
Ozkan S, Jindal S, Greenseid K, Shu J, Zeitlian G, Hickmon C, Pal L. 25:524 – 527.
Replete vitamin D stores predict reproductive success following in Somigliana E, Panina-Bordignon P, Murone S, Di Lucia P, Vercellini P,
vitro fertilization. Fertil Steril 2010;94:1314– 1319. Vigano P. Vitamin D reserve is higher in women with endometriosis.
Pal L, Berry A, Coraluzzi L, Kustan E, Danton C, Shaw J, Taylor H. Hum Reprod 2007;22:2273 – 2278.
Therapeutic implications of vitamin D and calcium in overweight Stumpf WE, Sar M, O’Brien LP. Vitamin D sites of action in the pituitary
women with polycystic ovary syndrome. Gynecol Endocrinol 2012, in studied by combined autoradiography-immunohistochemistry.
press. Histochemistry 1987a;88:11 – 16.
Panda DK, Miao D, Tremblay ML, Sirois J, Farookhi R, Hendy GN, Stumpf WE, Sar M, Chen K, Morin J, DeLuca HF. Sertoli cells in the testis and
Goltzman D. Targeted ablation of the 25-hydroxyvitamin D 1alpha epithelium of the ductuli efferentes are targets for 3H 1,25 (OH)2 vitamin
-hydroxylase enzyme: evidence for skeletal, reproductive, and immune D3. An autoradiographic study. Cell Tissue Res 1987b;247:453–455.
dysfunction. Proc Natl Acad Sci USA 2001;98:7498– 7503. Sun W, Xie H, Ji J, Zhou X, Goltzman D, Miao D. Defective female
Panda DK, Miao D, Bolivar I, Li J, Huo R, Hendy GN, Goltzman D. reproductive function in 1,25(OH)2D-deficient mice results from
Inactivation of the 25-hydroxyvitamin D 1alpha-hydroxylase and indirect effect mediated by extracellular calcium and/or phosphorus.
vitamin D receptor demonstrates independent and interdependent Am J Physiol Endocrinol Metab 2010;299:E928– E935.
Vitamin D in reproduction 3027

Thys-Jacobs S, Donovan D, Papadopoulos A, Sarrel P, Bilezikian JP. metabolic disturbances in polycystic ovary syndrome. Eur J Endocrinol
Vitamin and calcium dysregulation in the polycystic ovarian syndrome. 2009;161:575 – 582.
Steroids 1999;64:430– 435. Weisman Y, Harell A, Edelstein S, David M, Spirer Z, Golander A. 1 alpha,
Uhland AM, Kwiecinski GG, DeLuca HF. Normalization of serum calcium 25-Dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 in vitro
restores fertility in vitamin D-deficient male rats. J Nutr 1992; synthesis by human decidua and placenta. Nature 1979;281:317 – 319.
122:1338– 1344. Whitehouse A, Holt B, Serralha M, Holt P, Kusel M, Hart P. Maternal
Urrutia RP, Thorp JM. Vitamin D in pregnancy: current concepts. Curr Opin serum vitamin D levels during pregnancy and offspring neurocognitive
Obstet Gynecol 2012;24:57 –64. development. Pediatrics 2012;129:485 – 493.
Vienonen A, Miettinen S, Bläuer M, Martikainen PM, Tomás E, Heinonen PK Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF.
et al. Expression of nuclear receptors and cofactors in human Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 2000;
endometrium and myometrium. J Soc Gynecol Investig 2004;11:104–112. 72:690– 693.
Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, Yoshida M, Kawano N, Yoshida K. Control of sperm motility and fertility:
and safety. Am J Clin Nutr 1999;69:842 – 856. diverse factors and common mechanisms. Cell Mol Life Sci 2008;

Downloaded from https://academic.oup.com/humrep/article-abstract/27/10/3015/747482 by guest on 22 May 2019

Villamor E, Marin C, Mora-Plazas M, Baylin A. Vitamin D deficiency and 65:3446– 3457.
age at menarche: a prospective study. Am J Clin Nutr 2011; Yoshizawa T, Handa Y, Uematsu Y, Takeda S, Sekine K, Yoshihara Y,
94:1020– 1025. Kawakami T, Arioka K, Sato H, Uchiyama Y et al. Mice lacking the
Visser JA, de Jong FH, Laven JS, Themmen AP. Anti-Mullerian hormone: a Vitamin D receptor exhibit impaired bone formation, uterine
new marker for ovarian function. Reproduction 2006;131:1 – 9. hypoplasia and growth retardation after weaning. Nat Genet 1997;
Walters MR. Newly identified actions of the vitamin D endocrine system. 16:391– 396.
Endocr Rev 1992;13:719 – 763. Yu CKH, Ertl R, Skyfta E, Akolekar R, Nicolaides KH. Maternal serum
Wang J, Yang F, Mao M, Liu DH, Yang HM, Yang SF. High prevalence of vitamin D levels at 11 – 13 weeks of gestation and preeclampsia.
vitamin D and calcium deficiency among pregnant women and their J Hum Hypertens 2012 [Epub ahead of press].
newborns in Chengdu, China. World J Pediatr 2010;6:265– 267. Zarnani AH, Shahbazi M, Salek-Moghaddam A, Zareie M, Tavakoli M,
Wecksler WR, Norman AW. A kinetic and equilibrium binding study of 1 Ghasemi J, Rezania S, Moravej A, Torkabadi E, Rabbani H et al.
alpha,25-dihydroxyvitamin D3 with its cytosol receptor from chick Vitamin D(3) receptor is expressed in the endometrium of cycling
intestinal mucosa. J Biol Chem 1980a;255:3571 – 3574. mice throughout the estrous cycle. Fertil Steril 2010;93:2738 – 2743.
Wecksler WR, Norman AW. Measurement of kinetic rate constants for Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM,
the binding of 1 alpha, 25-dihydroxyvitamin D3 to its chick intestinal Hewison M. Extrarenal expression of 25-hydroxyvitamin d(3)-1
mucosa receptor using a hydroxyapatite batch assay. Methods Enzymol alpha-hydroxylase. J Clin Endocrinol Metab 2001;86:888 – 894.
1980b;67:488– 494. Zemel MB. Regulation of adiposity and obesity risk by dietary
Wecksler WR, Ross FP, Mason RS, Norman AW. Biochemical properties of calcium: mechanisms and implications. J Am Coll Nutr 2002;
the 1 alpha, 25-dihydroxyvitamin D3 cytosol receptors from human and 21:146S– 151S.
chicken intestinal mucosa. J Clin Endocrinol Metab 1980;50:152–157. Zhang C, Qui C, Hu FB, David Rm, Van Dam Rm, Bralley A, Williams MA.
Wehr E, Pilz S, Schweighofer N, Giuliani A, Kopera D, Pieber TR, Maternal plasma 25-hydroxyvitamin D concentrations and the risk for
Obermayer-Pietsch B. Association of hypovitaminosis D with gestational diabetes mellitus. PLos One 2008;3:e3753.