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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
discussion forum for
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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

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women in North America being deficient (9). The recently revised 4. Effect of vitamin D supplementation on clinical markers
guidelines of the Endocrine Society of North America defined of ovarian reserve
vitamin D deficiency as 25OH-D levels <20 ng/mL and 5. Association of vitamin D deficiency to factors respon-
insufficiency as levels of 20–30 ng/mL (9). In addition to its skeletal sible for ovulatory dysfunction (such as insulin resis-
effect (10), vitamin D has a wide range of actions that include cell tance [IR], hyperandrogenism, obesity, and metabolic
differentiation, apoptosis, antiproliferation, immunosuppression, syndrome) in women with PCOS
and antiinflammation (11, 12). Along with an appreciation of a 6. Effect of vitamin D supplementation to vitamin D-defi-
global epidemic of vitamin D deficiency (9), there has been an cient women with PCOS on serum AMH and the antiin-
increasing recognition that vitamin D plays an important role in flammatory soluble receptor for advanced glycation
female reproduction (13). For example, during pregnancy, end-products (sRAGE)
vitamin D deficiency has been related to increased risks of 7. Relationship between vitamin D levels and ovarian
gestational diabetes, recurrent pregnancy loss, preeclampsia, and response to ART (including number of oocytes retrieved,
small-for-gestational-age babies (14–18). The purpose of the embryo quality, and clinical pregnancy rate)
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 RESULTS
reserve markers, ovulatory dysfunction in polycystic ovary Supplemental Figure 2 (available online at www.fertstert.org)
syndrome (PCOS), and ovarian response to assisted reproductive summarizes the number of publications that were identified
technology (ART). during the initial search, and the number of publications
that were selected for inclusion after reviewing the titles
and abstracts.
MATERIALS AND METHODS
Search Strategy, Data Extraction, and Eligibility Vitamin D and Its Relationship to Markers of
Criteria Ovarian Reserve, Steroidogenesis, and Follicular
A systematic review of in vitro and in vivo, prospective and Development
retrospective, basic science and clinical, studies available in
A relationship exists between vitamin D and markers of
Pubmed for relevant publications in English through
ovarian reserve. Although AMH is one of the best markers
February 2014 was performed. In addition to ‘‘vitamin D,’’
for ovarian reserve, its expression and serum levels are altered
the following search terms were used: ‘‘ovary,’’ ‘‘granulosa
by environmental factors, such as vitamin D deficiency and
cell,’’ ‘‘follicle,’’ ‘‘steroidogenesis,’’ ‘‘progesterone,’’ ‘‘estra-
obesity (19–22). Vitamin D has been shown in animal
diol,’’ ‘‘ovarian reserve,’’ ‘‘advanced glycation end-products,’’
models to play a role in ovulatory dysfunction, likely
‘‘insulin resistance (IR),’’ ‘‘hyperandrogenism,’’ ‘‘obesity,’’
mediated through AMH gene (23). Additionally, the effect
‘‘metabolic syndrome,’’ ‘‘antim€ ullerian hormone (AMH),’’
of vitamin D on markers of ovarian reserve, as represented
‘‘PCOS,’’ and ‘‘IVF.’’ In addition, references from all relevant
by serum AMH, has been investigated (21, 24, 25).
articles were checked and hand searches of the abstracts of
AMH is a glycoprotein that belongs to the transforming
annual meetings of the American Society for Reproductive
growth factor family (26). It is produced by granulosa cells
Medicine and the European Society for Human Reproduction
of primary, preantral, and small antral follicles in the ovaries
and Embryology performed. The searches were conducted
and then secreted in the blood (26). AMH inhibits the loss of
independently by both authors. Disagreements were resolved
the oocyte pool by inhibiting the recruitment of primordial
by discussion and consensus. Titles and abstracts of all cita-
follicles and slowing down growth that is followed by atresia
tions identified in the search were reviewed. The full-text
and death of follicles containing the oocytes (26). Thus, AMH
article was retrieved if either reviewer considered the citation
gene null mutation causes early depletion of the stock of the
potentially relevant to ovarian physiology. Data were ex-
oocyte pool in the mouse ovary (27).
tracted from the text, tables, and graphs in the manuscripts.
In women, AMH is measured in the circulation, where it
The reference lists of identified articles were searched for
peaks a few years after puberty and subsequently declines
additional references. All data were abstracted and put into
with age, likely reflecting the age-related decline in ovarian
a table format in a systematic manner. Exclusion criteria
reserve (28). The insignificant fluctuation of AMH during
included editorials, case reports, letters to editors, duplicate
the menstrual cycle and arguably its superiority gives it an
publications, and studies pertaining to male subjects.
advantage over other ovarian reserve markers (such as day
3 FSH and day 3 inhibin), making it clinically useful and
Outcome Measures convenient for patients (26). There is a relationship between
vitamin D and steroidogenesis and between vitamin D and
Main outcomes of this systematic review included: AMH at both cellular and serum levels (Fig. 1; Table 1).
1. Effect of vitamin D on genes involved in steroidogenesis Cellular level. In a human prostate cancer cell line, Krishnan
and follicular development et al. (29) demonstrated that calcitriol treatment in vitro up-
2. Effect of vitamin D on markers of ovarian reserve regulated AMH messenger RNA (mRNA) expression levels.
3. Correlation of serum vitamin D with serum markers of Those investigators subsequently identified a functional
ovarian reserve vitamin D response element (VDRE) in the promoter region

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c-Kit ligand mRNA levels. Although there were increases in


FIGURE 1
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-
€llerian hormone (AMH) and
ally up-regulated during primordial follicle assembly and
Effect of vitamin D on serum antimu
AMH/AMH receptor II gene expression. PCOS ¼ polycystic ovary down-regulated during the primordial to primary follicle
syndrome. transition (36, 37). By inhibiting AMHR-II expression and
Irani. Vitamin D and ovarian physiology. Fertil Steril 2014. 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
of human AMH gene, thus demonstrating a potential direct ef- maturation and ovulation (Supplemental Fig. 3, available on-
fect of vitamin D on AMH expression (30). However, in line at www.fertstert.org) (38, 39). These findings suggest that
another recent in vitro study, Wojtusik and Johnson (31) tested vitamin D might promote the differentiation and development
whether 1,25-dihydroxyvitamin D3 regulates AMH mRNA of human granulosa cells.
expression in granulosa cells of the hen, and found the oppo- Serum level. A cross-sectional study by Merhi et al. (22) was
site of what happened in the prostate cancer cell line, i.e., 1,25- conducted to test the hypothesis that circulating 25OH-D is
dihydroxyvitamin D3 significantly decreased AMH mRNA positively correlated with serum AMH levels in a large cohort
expression levels. Additionally, there was a statistically of women with human immunodeficiency virus (HIV) and
significant enhancement of granulosa cell proliferation risk-matched HIV-noninfected women. Premenopausal
of 3–5 mm and 6–8 mm follicles incubated with 1,25- women (n ¼ 388) with regular menstrual cycles, who were
dihydroxyvitamin D3 at doses of 10 nmol/L and 100 nmol/L. either HIV positive or high-risk negative, were included. Par-
The authors also reported an increase in VDR mRNA and pro- ticipants were subdivided into three age groups: <35 years
tein levels following 1,25-dihydroxyvitamin D3 treatment. (n ¼ 128), 35–39 years (n ¼ 119), and R40 years (n ¼
Merhi et al. (22) conducted a study in humans, showing 141). A multivariate linear regression analysis showed that
that 1,25-dihydroxyvitamin D3 alters AMH sensitivity in serum 25OH-D was positively correlated with serum AMH
granulosa cells obtained from women who underwent oocyte levels in late-reproductive-age women (R40 years old;
retrieval for IVF. In that study, an inverse relationship be- regression slope ¼ þ0.011; P¼ .028).
tween follicular fluid 25OH-D and AMH receptor (AMHR-II) Of importance is the fact that there is a seasonal variation
gene expression was found: There was a twofold increase in in serum AMH (being 18% lower in the winter than in the
AMHR-II expression in granulosa cells of women with insuf- summer) that correlated with changes in seasonal serum
ficient/deficient follicular fluid 25OH-D (<30 ng/mL) 25OH-D (24). Additionally, Dennis et al. (24) demonstrated
compared with those with replete follicular fluid 25OH-D that the extent of seasonal variation in a woman's level of
levels (R30 ng/mL). Cumulus granulosa cells cultured with AMH correlated with the extent to which her 25OH-D levels
1,25-dihydroxyvitamin D3 showed a statistically significant varied. That study also proved that 1,25-dihydroxyvitamin
32% decrease in AMHR-II mRNA levels, 18% decrease in D3 supplements were sufficient to block the seasonal changes
FSH receptor (FSHR) mRNA levels, and 36% increase in 3- in both 25OH-D and AMH levels (24). Irani et al. (25) recently
beta-hydroxysteroid dehydrogenase (3b-HSD) mRNA levels conducted a prospective study to test the hypothesis that
(P< .05; Fig. 2). Culture with 1,25-dihydroxyvitamin D3 did 1,25-dihydroxyvitamin D3 supplementation normalizes
not cause a change in AMH, aromatase, LH receptor, or serum AMH levels in vitamin D–deficient premenopausal

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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 who underwent oocyte retrieval for IVF and found that follic-
PCOS were supplemented with oral 1,25-dihydroxyvitamin ular fluid sRAGE levels were positively correlated with gonad-
D3 (50,000 IU once weekly for 8 weeks), but there was no otropin dose needed per cycle, number of oocytes retrieved,
significant change in serum AMH levels (P¼ .6) (25). and follicular fluid AMH levels. That study suggested that
follicular fluid sRAGE could represent a possible measure of
Vitamin D and Factors Related to Ovulatory ovarian reserve (52).
Dysfunction in PCOS Vitamin D and sRAGE. AGEs have been shown to be
There might be a relationship between vitamin D deficiency and involved in the pathogenesis of PCOS, and their serum levels
PCOS phenotype (40–43). First, several studies have are elevated in women with PCOS (51, 53). AGEs accumulate
demonstrated that vitamin D deficiency is more common in in ovarian theca and granulosa layers of women with PCOS
women with PCOS compared with control women (44, 45). (54). This accumulation may be implicated in worsening
Second, vitamin D deficiency might be a contributing factor to ovarian follicular growth. Interestingly, in a recent study by
IR, obesity, and metabolic syndrome, all of which are Irani et al. (25) where 16 vitamin D–deficient women with
commonly observed in PCOS and associated with ovulatory PCOS were treated with oral 1,25-dihydroxyvitamin D3 for
dysfunction (Fig. 3; Table 1) (40–43). Interestingly, vitamin D 8 weeks, the significant increase in serum 25OH-D following
supplementation might improve menstrual irregularity, replacement was associated with: 1) a significant increase in
follicular development, and pregnancy rate in women with sRAGE levels, and 2) a significant decrease in the abnormally
PCOS (46–49). elevated serum AMH levels that are usually observed in PCOS
Advanced glycation end-products (AGEs) are the prod- (25). The increase in sRAGE is usually beneficial because it
ucts of the nonenzymatic modification of proteins, lipids, binds circulating AGEs and inhibits their inflammatory dele-
and nucleic acids by glucose (50). AGEs are proinflammatory terious effects (51). Lower serum AMH level in PCOS might
molecules that may play a role in abnormal follicular devel- potentially improve the ovulatory process because it de-
opment by binding to their cellular receptor (51). On the other creases intrafollicular androgens and increases follicular
hand, the soluble receptor sRAGE circulates and binds to sensitivity to FSH (Supplemental Fig. 3) (39, 55).
AGEs as a decoy, potentially preventing their harmful effect Vitamin D and insulin resistance. Although inconsistent,
on follicular health (51). Merhi et al. (52) studied 33 women several studies have shown that there is an inverse correlation

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polymorphisms have been correlated with PCOS parameters,


FIGURE 2
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
Role of vitamin D in human luteinized granulosa cells. Vitamin D who had an increase in 25OH-D levels following vitamin D
down-regulates FSH receptor (FSHR) and antimu €llerian hormone replacement experienced greater reductions in cholesterol
(AMH) receptor II (AMHR-II) mRNA levels. It also decreases Smad 1/ and waist circumference compared with those who had a
5/8 phosphorylation and nuclear translocation. Additionally, vitamin decrease in 25OH-D (80).
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. Vitamin D and IVF Outcome
The relationship between vitamin D levels and IVF outcomes,
between 25OH-D and IR, obesity, and free androgen index particularly clinical pregnancy rates (CPRs), has been assessed
(40–44, 56–63). Additionally, several studies have shown that in several studies with conflicting results (81–87). Ozkan et al.
vitamin D supplementation might improve IR and reduce (81) investigated the relationship in a cohort study of 84
serum androgens (63–68). A recent randomized controlled infertile women who underwent IVF. In patients who
trial has shown that correcting vitamin D deficiency in obese exhibited higher serum and follicular fluid 25OH-D levels,
adolescents was associated with significant improvement in there were higher implantation rates and a significantly
insulin sensitivity (65). higher CPR following embryo transfer (P¼ .04). Further
analysis showed that each 1-ng/mL increase in follicular fluid
Vitamin D receptor polymorphism and PCOS. Vitamin D
25OH-D increased the chance for achieving CPR by 6%
receptor polymorphism may be related to the pathophysi-
(P¼ .01) (81). Similarly, normal serum 25OH-D (R30 ng/
ology of PCOS (42, 69, 70), and VDR-related polymorphism
mL) was associated with higher CPR in recipients of oocyte
might be involved in PCOS susceptibility (69). Multiple VDR
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
FIGURE 3 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
Association of vitamin D deficiency with factors related to ovulatory elevated follicular fluid 25OH-D was associated with a worse
dysfunction in polycystic ovary syndrome (PCOS).
IVF outcome regarding number of oocytes retrieved and qual-
Irani. Vitamin D and ovarian physiology. Fertil Steril 2014.
ity of embryos formed. They conducted a study (n ¼ 101) to

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determine whether 25OH-D and glucose (as an energy source earlier findings (23) regarding steroidogenesis and vitamin D,
for oocytes) levels correlated with IVF outcome. They reported but also suggest that vitamin D may play a role in enhancing
a small nonsignificant increase in number of collected certain key steroidogenic enzymes such as 3b-HSD. During
oocytes among women with higher follicular fluid 25OH-D the normal menstrual cycle, luteinized human granulosa cells
levels. They also showed a significantly poorer quality of em- usually form the corpus luteum which produces large amounts
bryos in women replete with vitamin D (25OH-D >30 ng/mL). of progesterone (and some estrogens) and induces endometrial
Taking into consideration this negative association between changes such as decidualization to support a pregnancy.
25OH-D levels and embryo quality, Anifandis et al. (86) sug- Our summary of the literature suggests that 1,25-
gested that high vitamin D levels may negatively affect the dihydroxyvitamin D3 may potentiate granulosa cell luteiniza-
developmental capabilities of embryos, which would result tion as reflected by increased progesterone production, thus
in poorer IVF outcome. Finally, Firouzabadi et al. (87) studied providing a better endometrial environment. Whether this is
221 women who underwent IVF and reported no correlation clinically relevant still needs to be determined in vivo.
between pregnancy rate and either serum or follicular fluid Vitamin D and ovarian reserve. In the serum, the positive
25OH-D levels. correlation existing between circulating vitamin D and
AMH suggests a novel relationship between this vitamin
DISCUSSION and a clinically useful marker of ovarian reserve. The fact
To date, there are in vivo and in vitro data demonstrating that that vitamin D supplementation prevented the seasonal
there might be a relationship between vitamin D deficiency and changes in serum AMH strongly indicates that AMH produc-
ovarian physiology in both other animals and humans. These tion in adults may be regulated by vitamin D. Thus, assess-
data encompass granulosa cell physiology as well as women ment of vitamin D status, theoretically, might be considered
suffering from PCOS and infertile women undergoing ART. 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
Vitamin D and Follicular Development and better ovarian follicular dynamics. However, most of the
In the hen's ovaries, vitamin D down-regulated AMH gene and studies to date used markers of ovarian reserve/function
up-regulated FSHR gene expression. An explanation of these rather than pregnancy as an outcome, which limits the trans-
findings is as follows: During a women's follicular phase, the lational significance of the findings.
follicle that contains the most number of FSH receptors, there- Vitamin D and ovulatory dysfunction in PCOS. In PCOS,
fore that is most sensitive to FSH, emerges as dominant at the ovarian physiology is tightly linked to the metabolic distur-
time of intercycle FSH rise during the follicular phase. By in- bances observed in this disease; therefore, a beneficial effect
hibiting AMH expression, vitamin D may counteract the of vitamin D on the metabolic alterations might translate
repressive effects of AMH on granulosa cell differentiation, into a better and healthier ovarian physiology (40–42). Most
thereby allowing follicles to reach terminal maturation and PCOS women are either obese or overweight, making it
ovulation. A reason for the conflicting results seen between difficult to conclude that vitamin D deficiency contributes
prostate cancer cell line studies (where vitamin D was found to the pathogenesis of PCOS independently from elevated
to down-regulate AMH gene) and hen granulosa cells studies BMI. Obesity may decrease circulating 25OH-D by trapping
could be explained by differences in sex and species. this lipophilic vitamin in the adipose tissue. Therefore, the
In human luteinized granulosa cells, vitamin D decreased favorable effects of vitamin D on the metabolic alterations
AMHR-II and FSHR gene expression. Following follicular se- in PCOS, including the increase in antiinflammatory
lection in a women's late follicular phase, the follicle becomes sRAGE, might translate into an improvement in ovarian
less dependent on FSH and more dependent on LH, followed physiology. Vitamin D supplementation thus holds a
by terminal maturation and ovulation (27). Similarly to promise of becoming a potential therapeutic adjunct for the
AMHR-II, FSHR expression in granulosa cells has been found ovulatory dysfunction and metabolic alterations observed in
to be the highest in small immature follicles and gradually women with PCOS (71–73). Although data to date look
diminishes during folliculogenesis (27). FSHR expression promising, there is an urgent need for well designed
decreases along with the progression of maturation of oocytes randomized controlled trials to further analyze and evaluate
after hCG administration. It is not clear if the mechanistic the direct effect of oral vitamin D supplementation on long-
effect of vitamin D on FSHR is happening via AMH signaling. term ovarian physiology and metabolic alterations seen in
It is well documented that there is an interaction and strong vitamin D–deficient women with PCOS.
positive correlation between AMHR-II and FSHR gene expres-
sion in humans (27). It could be that vitamin D alters common Vitamin D and IVF. The relationship between vitamin D
intracellular mechanistic pathways involved in the regulation levels and IVF outcomes, particularly CPRs, has been incon-
of both AMHR-II and FSHR. Clearly, a complicated interrela- sistent in the literature. A possible reason for the discrepancy
tionship exists between these parameters. 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-
Vitamin D and Steroidogenesis tivity. Therefore, there are insufficient data to accurately
Vitamin D application in vitro increased 3b-HSD mRNA levels conclude the effect of vitamin D supplementation to vitamin
and progesterone production. These findings not only confirm D–depleted women undergoing IVF.

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CONCLUSION 10. Lips P, Bouillon R, van Schoor NM, Vanderschueren D, Verschueren S,


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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