ORIGINAL ARTICLES: ENVIRONMENT AND EPIDEMIOLOGY

Role of vitamin D in ovarian

physiology and its implication in
reproduction: a systematic review
Mohamad Irani, M.D.,a and Zaher Merhi, M.D.b
a
Department of Obstetrics and Gynecology, Maimonides Medical Center, Brooklyn, New York; and b Division of
Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences,
University of Vermont College of Medicine, Burlington, Vermont

Objective: To report an update on the role of vitamin D (VD) in ovarian physiology with a focus on genes involved in steroidogenesis,
follicular development, and ovarian reserve, as well as ovulatory dysfunction associated with polycystic ovary syndrome (PCOS), and
ovarian response to assisted reproductive technology (ART).
Design: Systematic review.
Setting: Not applicable.
Patient(s): Human, animal, and cell culture models.
Intervention(s): Pubmed literature search.
Main Outcome Measure(s): Granulosa cell function, serum antim€ ullerian hormone (AMH), AMH and its receptor gene expression, sol-
uble receptor for advanced glycation end-products (sRAGE), PCOS parameters, and ART outcome.
Result(s): In human granulosa cells, VD alters AMH signaling, FSH sensitivity, and progesterone production and release, indicating a
possible physiologic role for VD in ovarian follicular development and luteinization. In the serum, 25-hydroxyvitamin D (25OH-D) is
positively correlated with AMH, and appropriate VD supplementation in VD-depleted women can suppress the seasonal changes that
occur in serum AMH. In VD-deficient women with PCOS, VD supplementation lowers the abnormally elevated serum AMH levels,
possibly indicating a mechanism by which VD improves folliculogenesis. The antiinflammatory sRAGE serum levels significantly
increase in women with PCOS after VD replacement. Although follicular fluid 25OH-D correlates with IVF outcomes, there is a lack
of data pertaining to the impact of VD supplementation on pregnancy rates following IVF.
Conclusion(s): This review underscores the need for understanding the mechanistic actions of VD in ovarian physiology and the crit-
ical need for randomized trials to elucidate the impact of VD supplementation on controlled
ovarian hyperstimulation/IVF outcome and ovulatory dysfunction associated with PCOS. (Fertil Use your smartphone
SterilÒ 2014;102:460–8. Ó2014 by American Society for Reproductive Medicine.) to scan this QR code
Key Words: Vitamin D, steroidogenesis, folliculogenesis, ovarian reserve, AMH, PCOS, IVF and connect to the
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V
itamin D is a steroid hormone, droxylase to the active form 1,25- org). The biologic actions of vitamin D
synthesized mainly by the skin dihydroxyvitamin D3. The renal are mediated through vitamin D recep-
on exposure to ultraviolet light, enzyme 1a-hydroxylase is found in tor (VDR); which is a member of the ste-
with <10%–20% coming from diet other tissues, such as ovaries, brain, roid/thyroid nuclear hormone receptor
(1, 2). Vitamin D is converted to 25- breast, prostate, and colon, thus permit- superfamily (3, 4). VDR has been
hydroxyvitamin D (25OH-D) by hepatic ting the local synthesis of the active identified not only in calcium-
25-hydroxylase. Then circulating form of vitamin D (Supplemental regulating tissues such as the intestines,
25OH-D gets converted by renal 1a-hy- Fig. 1, available online at www.fertstert. skeleton, and parathyroid glands, but
also in many other reproductive organs,
Received February 28, 2014; revised and accepted April 30, 2014; published online June 3, 2014. such as ovary (particularly granulosa
M.I. has nothing to disclose. Z.M. has nothing to disclose. cells), uterus, placenta, testis, hypo-
Supported by grants from Ferring Pharmaceutical, American Society for Reproductive Medicine, and
University of Vermont College of Medicine. thalamus, and pituitary (5–8). This
Reprint requests: Zaher Merhi, M.D., Assistant Professor, Reproductive Endocrinology and Infertility, diverse expression of VDR suggests a
University of Vermont College of Medicine, Burlington, Vermont 05405 (E-mail: zom00@hotmail.
com). potential role of vitamin D in female
reproductive physiology (4).
Fertility and Sterility® Vol. 102, No. 2, August 2014 0015-0282/$36.00 Vitamin D deficiency is very com-
Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.fertnstert.2014.04.046 mon, with 20%–90% of reproductive-age

460 VOL. 102 NO. 2 / AUGUST 2014


women in North America being deficient (9). The recently revised
guidelines of the Endocrine Society of North America defined
vitamin D deficiency as 25OH-D levels <20 ng/mL and
insufficiency as levels of 20–30 ng/mL (9). In addition to its skeletal
effect (10), vitamin D has a wide range of actions that include cell
differentiation, apoptosis, antiproliferation, immunosuppression,
and antiinflammation (11, 12). Along with an appreciation of a
global epidemic of vitamin D deficiency (9), there has been an
increasing recognition that vitamin D plays an important role in
female reproduction (13). For example, during pregnancy,
vitamin D deficiency has been related to increased risks of
gestational diabetes, recurrent pregnancy loss, preeclampsia, and
small-for-gestational-age babies (14–18). The purpose of the
present systematic review is to report the dynamics and role of
vitamin D on ovarian physiology, with a focus on genes
involved in steroidogenesis, follicular development, ovarian
reserve markers, ovulatory dysfunction in polycystic ovary
syndrome (PCOS), and ovarian response to assisted reproductive
technology (ART).
MATERIALS AND METHODS
Search Strategy, Data Extraction, and Eligibility
Criteria
A systematic review of in vitro and in vivo, prospective and
retrospective, basic science and clinical, studies available in
Pubmed for relevant publications in English through
February 2014 was performed. In addition to ‘‘vitamin D,’’
the following search terms were used: ‘‘ovary,’’ ‘‘granulosa
cell,’’ ‘‘follicle,’’ ‘‘steroidogenesis,’’ ‘‘progesterone,’’ ‘‘estra-
diol,’’ ‘‘ovarian reserve,’’ ‘‘advanced glycation end-products,’’
‘‘insulin resistance (IR),’’ ‘‘hyperandrogenism,’’ ‘‘obesity,’’
‘‘metabolic syndrome,’’ ‘‘antim€ ullerian hormone (AMH),’’
‘‘PCOS,’’ and ‘‘IVF.’’ In addition, references from all relevant
articles were checked and hand searches of the abstracts of
annual meetings of the American Society for Reproductive
Medicine and the European Society for Human Reproduction
and Embryology performed. The searches were conducted
independently by both authors. Disagreements were resolved
by discussion and consensus. Titles and abstracts of all cita-
tions identified in the search were reviewed. The full-text
article was retrieved if either reviewer considered the citation
potentially relevant to ovarian physiology. Data were ex-
tracted from the text, tables, and graphs in the manuscripts.
The reference lists of identified articles were searched for
additional references. All data were abstracted and put into
a table format in a systematic manner. Exclusion criteria
included editorials, case reports, letters to editors, duplicate
publications, and studies pertaining to male subjects.
Outcome Measures
Main outcomes of this systematic review included:
1. Effect of vitamin D on genes involved in steroidogenesis
and follicular development
2. Effect of vitamin D on markers of ovarian reserve
3. Correlation of serum vitamin D with serum markers of
ovarian reserve
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Fertility and Sterility®
4. Effect of vitamin D supplementation on clinical markers
of ovarian reserve
5. Association of vitamin D deficiency to factors respon-
sible for ovulatory dysfunction (such as insulin resis-
tance [IR], hyperandrogenism, obesity, and metabolic
syndrome) in women with PCOS
6. Effect of vitamin D supplementation to vitamin D-defi-
cient women with PCOS on serum AMH and the antiin-
flammatory soluble receptor for advanced glycation
end-products (sRAGE)
7. Relationship between vitamin D levels and ovarian
response to ART (including number of oocytes retrieved,
embryo quality, and clinical pregnancy rate)
RESULTS
Supplemental Figure 2 (available online at www.fertstert.org)
summarizes the number of publications that were identified
during the initial search, and the number of publications
that were selected for inclusion after reviewing the titles
and abstracts.
Vitamin D and Its Relationship to Markers of
Ovarian Reserve, Steroidogenesis, and Follicular
Development
A relationship exists between vitamin D and markers of
ovarian reserve. Although AMH is one of the best markers
for ovarian reserve, its expression and serum levels are altered
by environmental factors, such as vitamin D deficiency and
obesity (19–22). Vitamin D has been shown in animal
models to play a role in ovulatory dysfunction, likely
mediated through AMH gene (23). Additionally, the effect
of vitamin D on markers of ovarian reserve, as represented
by serum AMH, has been investigated (21, 24, 25).
AMH is a glycoprotein that belongs to the transforming
growth factor family (26). It is produced by granulosa cells
of primary, preantral, and small antral follicles in the ovaries
and then secreted in the blood (26). AMH inhibits the loss of
the oocyte pool by inhibiting the recruitment of primordial
follicles and slowing down growth that is followed by atresia
and death of follicles containing the oocytes (26). Thus, AMH
gene null mutation causes early depletion of the stock of the
oocyte pool in the mouse ovary (27).
In women, AMH is measured in the circulation, where it
peaks a few years after puberty and subsequently declines
with age, likely reflecting the age-related decline in ovarian
reserve (28). The insignificant fluctuation of AMH during
the menstrual cycle and arguably its superiority gives it an
advantage over other ovarian reserve markers (such as day
3 FSH and day 3 inhibin), making it clinically useful and
convenient for patients (26). There is a relationship between
vitamin D and steroidogenesis and between vitamin D and
AMH at both cellular and serum levels (Fig. 1; Table 1).
Cellular level. In a human prostate cancer cell line, Krishnan
et al. (29) demonstrated that calcitriol treatment in vitro up-
regulated AMH messenger RNA (mRNA) expression levels.
Those investigators subsequently identified a functional
vitamin D response element (VDRE) in the promoter region
461
ORIGINAL ARTICLE: ENVIRONMENT AND EPIDEMIOLOGY
FIGURE 1
€llerian hormone (AMH) and
Effect of vitamin D on serum antimu
AMH/AMH receptor II gene expression. PCOS ¼ polycystic ovary
syndrome.
Irani. Vitamin D and ovarian physiology. Fertil Steril 2014.
of human AMH gene, thus demonstrating a potential direct ef-
fect of vitamin D on AMH expression (30). However, in
another recent in vitro study, Wojtusik and Johnson (31) tested
whether 1,25-dihydroxyvitamin D3 regulates AMH mRNA
expression in granulosa cells of the hen, and found the oppo-
site of what happened in the prostate cancer cell line, i.e., 1,25-
dihydroxyvitamin D3 significantly decreased AMH mRNA
expression levels. Additionally, there was a statistically
significant enhancement of granulosa cell proliferation
of 3–5 mm and 6–8 mm follicles incubated with 1,25-
dihydroxyvitamin D3 at doses of 10 nmol/L and 100 nmol/L.
The authors also reported an increase in VDR mRNA and pro-
tein levels following 1,25-dihydroxyvitamin D3 treatment.
Merhi et al. (22) conducted a study in humans, showing
that 1,25-dihydroxyvitamin D3 alters AMH sensitivity in
granulosa cells obtained from women who underwent oocyte
retrieval for IVF. In that study, an inverse relationship be-
tween follicular fluid 25OH-D and AMH receptor (AMHR-II)
gene expression was found: There was a twofold increase in
AMHR-II expression in granulosa cells of women with insuf-
ficient/deficient follicular fluid 25OH-D (<30 ng/mL)
compared with those with replete follicular fluid 25OH-D
levels (R30 ng/mL). Cumulus granulosa cells cultured with
1,25-dihydroxyvitamin D3 showed a statistically significant
32% decrease in AMHR-II mRNA levels, 18% decrease in
FSH receptor (FSHR) mRNA levels, and 36% increase in 3-
beta-hydroxysteroid dehydrogenase (3b-HSD) mRNA levels
(P< .05; Fig. 2). Culture with 1,25-dihydroxyvitamin D3 did
not cause a change in AMH, aromatase, LH receptor, or
462
c-Kit ligand mRNA levels. Although there were increases in
steroidogenic acute regulatory protein StAR (14%) and P450
side-chain cleavage enzyme (17%) mRNA levels, they did
not reach statistical significance (P¼ .2) (22). Despite these
findings, it is important to note that the terminally differenti-
ated granulosa cells (luteinized) obtained in that study after
controlled ovulation hyperstimulation might be functionally
distinct from granulosa cells of developing follicles.
Additionally, Merhi et al. (22) reported that treatment of
human granulosa cells with 1,25-dihydroxyvitamin D3
in vitro increased progesterone production in the presence
of the precursor substrate pregnenolone (22). Similarly,
Parikh et al. (32) has shown that vitamin D increased proges-
terone, estrogen, estrone, and insulin-like growth factor–
binding protein 1 production in human ovarian cells.
Moreover, 1,25-dihydroxyvitamin D3 stimulated estrogen
and progesterone production in human placenta (33).
AMH interacts with the highly specific AMHR-II and sig-
nals via Smad 1/5/8 (34, 35). 1,25-Dihydroxyvitamin D3 not
only down-regulated AMHR-II gene expression, but also
significantly reduced the phosphorylation of Smad 1/5/8
and its nuclear localization as expressed by immunofluores-
cence (22). Consistently with its inhibitory role, AMH is usu-
ally up-regulated during primordial follicle assembly and
down-regulated during the primordial to primary follicle
transition (36, 37). By inhibiting AMHR-II expression and
signaling, 1,25-dihydroxyvitamin D3 may counteract the
repressive effect of AMH on granulosa cell differentiation.
The lesser AMH sensitivity allows follicles to reach terminal
maturation and ovulation (Supplemental Fig. 3, available on-
line at www.fertstert.org) (38, 39). These findings suggest that
vitamin D might promote the differentiation and development
of human granulosa cells.
Serum level. A cross-sectional study by Merhi et al. (22) was
conducted to test the hypothesis that circulating 25OH-D is
positively correlated with serum AMH levels in a large cohort
of women with human immunodeficiency virus (HIV) and
risk-matched HIV-noninfected women. Premenopausal
women (n ¼ 388) with regular menstrual cycles, who were
either HIV positive or high-risk negative, were included. Par-
ticipants were subdivided into three age groups: <35 years
(n ¼ 128), 35–39 years (n ¼ 119), and R40 years (n ¼
141). A multivariate linear regression analysis showed that
serum 25OH-D was positively correlated with serum AMH
levels in late-reproductive-age women (R40 years old;
regression slope ¼ þ0.011; P¼ .028).
Of importance is the fact that there is a seasonal variation
in serum AMH (being 18% lower in the winter than in the
summer) that correlated with changes in seasonal serum
25OH-D (24). Additionally, Dennis et al. (24) demonstrated
that the extent of seasonal variation in a woman's level of
AMH correlated with the extent to which her 25OH-D levels
varied. That study also proved that 1,25-dihydroxyvitamin
D3 supplements were sufficient to block the seasonal changes
in both 25OH-D and AMH levels (24). Irani et al. (25) recently
conducted a prospective study to test the hypothesis that
1,25-dihydroxyvitamin D3 supplementation normalizes
serum AMH levels in vitamin D–deficient premenopausal
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 Fertility and Sterility®

TABLE 1

Role of vitamin D in ovarian physiology in animal, human, and cell line models.
Model Type of study
Association with genes that reflect follicular development and ovarian reserve
Human Vitamin D treatment in vitro down-regulates AMHR-II and FSHR gene expression In vitro
in human granulosa cells (22).
Vitamin D treatment in vitro attenuates the phosphorylation and nuclear In vitro
translocation of Smad 1/5/8 in human granulosa cells (22)
Vitamin D treatment in vitro up-regulates AMH mRNA expression in prostate In vitro
cancer cells (30)
Positive correlation between serum AMH and 25OH-D levels (24) Cohort
Hen Vitamin D treatment in vitro down-regulates AMH gene and up-regulates FSHR In vitro
gene expression in hen ovaries (31)
Association with steroidogenesis
Human Vitamin D increases 3b-HSD gene expression and increases P production by In vitro
human granulosa cells (22)
Vitamin D stimulates estrogen, P, and IGF-binding protein 1 production by In vitro
human ovarian cells (32)
Vitamin D increases estrogen and P production by human placental cells (33) In vitro
Association with factors related to ovulatory dysfunction in PCOS
Human Positive correlation between vitamin D deficiency and insulin resistance (40–44) Cross-sectional
Positive correlation between vitamin D deficiency and adiposity (73–77) Cross-sectional
Positive correlation between vitamin D deficiency and androgen levels (40) Cross-sectional
Human Improvement in menstrual irregularity and ovulation (46) Cohort
(vitamin D supplementation) Decrease in insulin resistance (65) Randomized
controlled trial
Decrease in androgen levels (63) Cohort
Normalization of elevated serum AMH levels (25) Cohort
Increase in antiinflammatory serum sRAGE levels (25) Cohort
Association with fertility and ART
Human Serum and follicular fluid 25OH-D levels are associated with higher clinical Cohort
pregnancy rates but poorer embryo quality following IVF (81–86)
Note: 25OH-D ¼ 25-hydroxyvitamin D; 3b-HSD ¼ 3-beta-hydroxysteroid dehydrogenase; AMH ¼ antimullerian hormone; AMHR-II ¼ AMH receptor; ART ¼ assisted reproductive technology;
FSHR ¼ FSH receptor; IVF ¼ in vitro fertilization; PCOS ¼ polycystic ovary syndrome; sRAGE ¼ soluble receptor for advanced glycation end-products.
Irani. Vitamin D and ovarian physiology. Fertil Steril 2014.

women. Forty-seven vitamin D–deficient women without
PCOS were supplemented with oral 1,25-dihydroxyvitamin
D3 (50,000 IU once weekly for 8 weeks), but there was no
significant change in serum AMH levels (P¼ .6) (25).
Vitamin D and Factors Related to Ovulatory
Dysfunction in PCOS
There might be a relationship between vitamin D deficiency and
PCOS phenotype (40–43). First, several studies have
demonstrated that vitamin D deficiency is more common in
women with PCOS compared with control women (44, 45).
Second, vitamin D deficiency might be a contributing factor to
IR, obesity, and metabolic syndrome, all of which are
commonly observed in PCOS and associated with ovulatory
dysfunction (Fig. 3; Table 1) (40–43). Interestingly, vitamin D
supplementation might improve menstrual irregularity,
follicular development, and pregnancy rate in women with
PCOS (46–49).
Advanced glycation end-products (AGEs) are the prod-
ucts of the nonenzymatic modification of proteins, lipids,
and nucleic acids by glucose (50). AGEs are proinflammatory
molecules that may play a role in abnormal follicular devel-
opment by binding to their cellular receptor (51). On the other
hand, the soluble receptor sRAGE circulates and binds to
AGEs as a decoy, potentially preventing their harmful effect
on follicular health (51). Merhi et al. (52) studied 33 women
who underwent oocyte retrieval for IVF and found that follic-
ular fluid sRAGE levels were positively correlated with gonad-
otropin dose needed per cycle, number of oocytes retrieved,
and follicular fluid AMH levels. That study suggested that
follicular fluid sRAGE could represent a possible measure of
ovarian reserve (52).
Vitamin D and sRAGE. AGEs have been shown to be
involved in the pathogenesis of PCOS, and their serum levels
are elevated in women with PCOS (51, 53). AGEs accumulate
in ovarian theca and granulosa layers of women with PCOS
(54). This accumulation may be implicated in worsening
ovarian follicular growth. Interestingly, in a recent study by
Irani et al. (25) where 16 vitamin D–deficient women with
PCOS were treated with oral 1,25-dihydroxyvitamin D3 for
8 weeks, the significant increase in serum 25OH-D following
replacement was associated with: 1) a significant increase in
sRAGE levels, and 2) a significant decrease in the abnormally
elevated serum AMH levels that are usually observed in PCOS
(25). The increase in sRAGE is usually beneficial because it
binds circulating AGEs and inhibits their inflammatory dele-
terious effects (51). Lower serum AMH level in PCOS might
potentially improve the ovulatory process because it de-
creases intrafollicular androgens and increases follicular
sensitivity to FSH (Supplemental Fig. 3) (39, 55).
Vitamin D and insulin resistance. Although inconsistent,
several studies have shown that there is an inverse correlation

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ORIGINAL ARTICLE: ENVIRONMENT AND EPIDEMIOLOGY
FIGURE 2
Role of vitamin D in human luteinized granulosa cells. Vitamin D
down-regulates FSH receptor (FSHR) and antimu €llerian hormone
(AMH) receptor II (AMHR-II) mRNA levels. It also decreases Smad 1/
5/8 phosphorylation and nuclear translocation. Additionally, vitamin
D induces 3-beta-hydroxysteroid dehydrogenase (3b-HSD) mRNA
expression and increases progesterone production and release.
Irani. Vitamin D and ovarian physiology. Fertil Steril 2014.
between 25OH-D and IR, obesity, and free androgen index
(40–44, 56–63). Additionally, several studies have shown that
vitamin D supplementation might improve IR and reduce
serum androgens (63–68). A recent randomized controlled
trial has shown that correcting vitamin D deficiency in obese
adolescents was associated with significant improvement in
insulin sensitivity (65).
Vitamin D receptor polymorphism and PCOS. Vitamin D
receptor polymorphism may be related to the pathophysi-
ology of PCOS (42, 69, 70), and VDR-related polymorphism
might be involved in PCOS susceptibility (69). Multiple VDR
FIGURE 3
Association of vitamin D deficiency with factors related to ovulatory
dysfunction in polycystic ovary syndrome (PCOS).
Irani. Vitamin D and ovarian physiology. Fertil Steril 2014.
464
polymorphisms have been correlated with PCOS parameters,
including VDR Apa-I, VDR Cd2, and VDR Taq-I (44, 69–
71). Some other genetic variants were correlated with PCOS
severity, but not with PCOS susceptibility (72).
Vitamin D and adiposity. Serum 25OH-D is negatively corre-
lated with body mass index (BMI), central obesity, and
adiposity measures (73–77). Based on a bidirectional genetic
analysis of multiple cohorts, obesity was associated with
vitamin D deficiency, but the effect of low 25OH-D on BMI
was minimal (78). Moreover, higher doses of 1,25-
dihydroxyvitamin D3 were required to treat vitamin D defi-
ciency in obese compared with normal-weight adolescents
(25, 79). After applying a 20-week lifestyle modification
program to 50 overweight/obese women with PCOS, those
who had an increase in 25OH-D levels following vitamin D
replacement experienced greater reductions in cholesterol
and waist circumference compared with those who had a
decrease in 25OH-D (80).
Vitamin D and IVF Outcome
The relationship between vitamin D levels and IVF outcomes,
particularly clinical pregnancy rates (CPRs), has been assessed
in several studies with conflicting results (81–87). Ozkan et al.
(81) investigated the relationship in a cohort study of 84
infertile women who underwent IVF. In patients who
exhibited higher serum and follicular fluid 25OH-D levels,
there were higher implantation rates and a significantly
higher CPR following embryo transfer (P¼ .04). Further
analysis showed that each 1-ng/mL increase in follicular fluid
25OH-D increased the chance for achieving CPR by 6%
(P¼ .01) (81). Similarly, normal serum 25OH-D (R30 ng/
mL) was associated with higher CPR in recipients of oocyte
donation compared with those with vitamin D-insuffi-
ciency/deficiency (25OH-D <30 ng/mL) (82). The latter study
suggested that vitamin D may be related to IVF outcome
through its impact on the endometrium (82).
A retrospective cohort study of 188 infertile women under-
going IVF showed a positive correlation between serum 25OH-D
levels and IVF success rate among non-Hispanic white women
(P¼ .04) (83). However, an opposite correlation was seen among
Asian women, where pregnancy rates were higher in those with
lower serum 25OH-D levels (P¼ .01) (83). Another study
conducted by Estes et al. (84) enrolled 2,688 couples before their
first IVF cycle to determine the predictors of IVF success. With
the use of proteomic analysis in the follicular fluid, they
compared 25OH-D levels in the follicular fluid of young women
(%32 years old) divided into two groups: those with good oocyte
retrieval results (R11 oocytes) who achieved live birth versus
those with poor oocyte retrieval results (<11 oocytes) who did
not achieve conception. They reported a lower expression of
vitamin D–binding protein (VDBP) in the follicular fluid in the
group that underwent successful IVF. However, serum and
follicular fluid 25OH-D levels did not correlate with IVF out-
comes (85).
Surprisingly, a study by Anifandis et al. (86) showed that
elevated follicular fluid 25OH-D was associated with a worse
IVF outcome regarding number of oocytes retrieved and qual-
ity of embryos formed. They conducted a study (n ¼ 101) to
VOL. 102 NO. 2 / AUGUST 2014

determine whether 25OH-D and glucose (as an energy source
for oocytes) levels correlated with IVF outcome. They reported
a small nonsignificant increase in number of collected
oocytes among women with higher follicular fluid 25OH-D
levels. They also showed a significantly poorer quality of em-
bryos in women replete with vitamin D (25OH-D >30 ng/mL).
Taking into consideration this negative association between
25OH-D levels and embryo quality, Anifandis et al. (86) sug-
gested that high vitamin D levels may negatively affect the
developmental capabilities of embryos, which would result
in poorer IVF outcome. Finally, Firouzabadi et al. (87) studied
221 women who underwent IVF and reported no correlation
between pregnancy rate and either serum or follicular fluid
25OH-D levels.
DISCUSSION
To date, there are in vivo and in vitro data demonstrating that
there might be a relationship between vitamin D deficiency and
ovarian physiology in both other animals and humans. These
data encompass granulosa cell physiology as well as women
suffering from PCOS and infertile women undergoing ART.
Vitamin D and Follicular Development
In the hen's ovaries, vitamin D down-regulated AMH gene and
up-regulated FSHR gene expression. An explanation of these
findings is as follows: During a women's follicular phase, the
follicle that contains the most number of FSH receptors, there-
fore that is most sensitive to FSH, emerges as dominant at the
time of intercycle FSH rise during the follicular phase. By in-
hibiting AMH expression, vitamin D may counteract the
repressive effects of AMH on granulosa cell differentiation,
thereby allowing follicles to reach terminal maturation and
ovulation. A reason for the conflicting results seen between
prostate cancer cell line studies (where vitamin D was found
to down-regulate AMH gene) and hen granulosa cells studies
could be explained by differences in sex and species.
In human luteinized granulosa cells, vitamin D decreased
AMHR-II and FSHR gene expression. Following follicular se-
lection in a women's late follicular phase, the follicle becomes
less dependent on FSH and more dependent on LH, followed
by terminal maturation and ovulation (27). Similarly to
AMHR-II, FSHR expression in granulosa cells has been found
to be the highest in small immature follicles and gradually
diminishes during folliculogenesis (27). FSHR expression
decreases along with the progression of maturation of oocytes
after hCG administration. It is not clear if the mechanistic
effect of vitamin D on FSHR is happening via AMH signaling.
It is well documented that there is an interaction and strong
positive correlation between AMHR-II and FSHR gene expres-
sion in humans (27). It could be that vitamin D alters common
intracellular mechanistic pathways involved in the regulation
of both AMHR-II and FSHR. Clearly, a complicated interrela-
tionship exists between these parameters.
Vitamin D and Steroidogenesis
Vitamin D application in vitro increased 3b-HSD mRNA levels
and progesterone production. These findings not only confirm
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Fertility and Sterility®
earlier findings (23) regarding steroidogenesis and vitamin D,
but also suggest that vitamin D may play a role in enhancing
certain key steroidogenic enzymes such as 3b-HSD. During
the normal menstrual cycle, luteinized human granulosa cells
usually form the corpus luteum which produces large amounts
of progesterone (and some estrogens) and induces endometrial
changes such as decidualization to support a pregnancy.
Our summary of the literature suggests that 1,25-
dihydroxyvitamin D3 may potentiate granulosa cell luteiniza-
tion as reflected by increased progesterone production, thus
providing a better endometrial environment. Whether this is
clinically relevant still needs to be determined in vivo.
Vitamin D and ovarian reserve. In the serum, the positive
correlation existing between circulating vitamin D and
AMH suggests a novel relationship between this vitamin
and a clinically useful marker of ovarian reserve. The fact
that vitamin D supplementation prevented the seasonal
changes in serum AMH strongly indicates that AMH produc-
tion in adults may be regulated by vitamin D. Thus, assess-
ment of vitamin D status, theoretically, might be considered
as part of the routine workup in infertile women. Addition-
ally, appropriate supplementation of patients with vitamin
D deficiency might translate to better ovarian reserve markers
and better ovarian follicular dynamics. However, most of the
studies to date used markers of ovarian reserve/function
rather than pregnancy as an outcome, which limits the trans-
lational significance of the findings.
Vitamin D and ovulatory dysfunction in PCOS. In PCOS,
ovarian physiology is tightly linked to the metabolic distur-
bances observed in this disease; therefore, a beneficial effect
of vitamin D on the metabolic alterations might translate
into a better and healthier ovarian physiology (40–42). Most
PCOS women are either obese or overweight, making it
difficult to conclude that vitamin D deficiency contributes
to the pathogenesis of PCOS independently from elevated
BMI. Obesity may decrease circulating 25OH-D by trapping
this lipophilic vitamin in the adipose tissue. Therefore, the
favorable effects of vitamin D on the metabolic alterations
in PCOS, including the increase in antiinflammatory
sRAGE, might translate into an improvement in ovarian
physiology. Vitamin D supplementation thus holds a
promise of becoming a potential therapeutic adjunct for the
ovulatory dysfunction and metabolic alterations observed in
women with PCOS (71–73). Although data to date look
promising, there is an urgent need for well designed
randomized controlled trials to further analyze and evaluate
the direct effect of oral vitamin D supplementation on long-
term ovarian physiology and metabolic alterations seen in
vitamin D–deficient women with PCOS.
Vitamin D and IVF. The relationship between vitamin D
levels and IVF outcomes, particularly CPRs, has been incon-
sistent in the literature. A possible reason for the discrepancy
among the studies was their outcomes, pregnancy and em-
bryo quality, which rely heavily on a multitude of factors,
such as sperm quality and quantity and endometrial recep-
tivity. Therefore, there are insufficient data to accurately
conclude the effect of vitamin D supplementation to vitamin
D–depleted women undergoing IVF.
465
ORIGINAL ARTICLE: ENVIRONMENT AND EPIDEMIOLOGY
CONCLUSION
Unveiling the effect of vitamin D in the ovary might poten-
tially lead to this oral, relatively safe, and cheap vitamin
becoming an adjunct agent in therapies for ovulatory
dysfunction commonly seen in PCOS and possibly for infer-
tility in all reproductive-age women. Direct effect of vitamin
D on the quality of human oocytes and embryos has not yet
been investigated. The present systematic review underscores
the need for randomized trials to elucidate the impact of
vitamin D supplementation on ovulation response to gonad-
otropins and IVF outcome, which should include: the number
of total and mature oocytes retrieved, the number and quality
of embryos formed, CPRs, and live birth rates. Over the past
decade, the field of ovarian reserve, as reflected by AMH,
has been enriched by data from numerous clinical investiga-
tions and experience. The potential focus and methods of
future clinical investigations should concern the influence
of vitamin D on ovarian reserve in women with diminished
ovarian reserve. Little is known about the contribution of
nutritional elements, such as vitamin D, to ovarian reserve
and how these elements can influence the process of ovarian
aging. Future contributions of vitamin D should have broad
significance to increase natural conception in women with
ovarian aging with an aim to decrease costs by either avoid-
ing the need for IVF or by lowering the number of IVF cycles
needed per patient. Additionally, the significance of this
subject will ultimately contribute to understanding the role
of vitamin D in menopause, which can be predicted by a
simple serum AMH testing that is strongly altered by
vitamin D (88, 89).
Acknowledgments: The authors thank Professor Howard
Minkoff, M.D., for his edits and comments on an earlier
version of the manuscript.
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SUPPLEMENTAL FIGURE 1

Summary of the origin and function of vitamin D. Reprinted by

permission from Dr. Frauke von Versen–Ho €ynck: Grundmann M,
von Versen–Ho €ynck F. Vitamin D—roles in women's reproductive
health? Reprod Biol Endocrinol 2011; 9:146.
Irani. Vitamin D and ovarian physiology. Fertil Steril 2014.

VOL. 102 NO. 2 / AUGUST 2014 468.e1

ORIGINAL ARTICLE: ENVIRONMENT AND EPIDEMIOLOGY

SUPPLEMENTAL FIGURE 2

Data search strategy.

Irani. Vitamin D and ovarian physiology. Fertil Steril 2014.

468.e2 VOL. 102 NO. 2 / AUGUST 2014

 Fertility and Sterility®

SUPPLEMENTAL FIGURE 3

Antimu€llerian hormone (AMH) inhibits FSH-induced follicular growth

in a paracrine fashion.
Irani. Vitamin D and ovarian physiology. Fertil Steril 2014.

VOL. 102 NO. 2 / AUGUST 2014 468.e3