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Vitamin D metabolism in polycystic ovary syndrome (PCOS)

Vitamin D metabolism
Vitamin D is a steroid hormone, synthesized mainly by the skin on exposure to natural sunlight, with < 10%–20% deriving from the diet . Vitamin D is
hydroxylated to 25-hydroxyvitamin D (25(OH)D) or calcifediol by the liver; then, calcifediol is converted by renal 1α-hydroxylase to the active form 1,25-
dihydroxyvitamin D3 [1,25-(OH) 2 D 3 ] or calcitriol. The enzyme 1α-hydroxylase is expressed in other tissues, such as ovaries, brain, breast, prostate, and
colon, thus permitting the local synthesis of the active form of vitamin D and paracrine effects . Calcitriol circulates in the blood bound to vitamin D-binding
protein until its target tissues where it acts via binding to the nuclear vitamin D receptor (VDR) . In a study on VDR binding throughout the human genome using
chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq), Ramagopalan et al. identified 2776 genomic positions occupied by
VDR and 229 genes significantly responsive to vitamin D stimulation in more than 30 different tissues, such as skeleton, brain, breast, pancreas, parathyroid
glands, immune cells, cardiomyocytes and reproductive organs, including ovaries, placenta, uterus, and testes .

The main physiologic role of vitamin D is to promote intestinal calcium absorption and to regulate osteoclast function, maintaining calcium/phosphorus
homeostasis and controlling bone mineralization; however, vitamin D has pleiotropic effects . In addition to its role in calcium-regulating tissues, vitamin D has
been implicated in a wide range of extra-skeletal effects such as glucose homeostasis, cardiovascular disease, cancer, reproductive dysfunctions, autoimmune
diseases, and endocrine conditions, including polycystic ovary syndrome (PCOS) .

The guidelines of the Endocrine Society defined vitamin D deficiency as 25(OH)D levels < 20 ng/mL and insufficiency as a level between 21 and 29 ng/mL .
Vitamin D deficiency is very common worldwide not only in the older population but also in the younger population . A relatively high prevalence of vitamin D
deficiency is observed in women with PCOS (about 67%–85%) .

Vitamin D and female reproductive physiology

The role of vitamin D pathway in the pathogenesis of PCOS can be understood by underlying the importance of this vitamin in the female reproductive
physiology, even if the exact underlying mechanism remains unclear . VDR is expressed in reproductive tissues of cycling mice, including endometrium, ovaries,
and fallopian tubes; in pregnant mice, VDR is expressed also in the placenta and decidua . Furthermore, VDR knockout mice have impaired folliculogenesis,
hypergonadotropic hypogonadism with decreased aromatase activity and CYP19 gene expression . In humans, in vitro exposure of ovarian cells to vitamin D
increased the production of progesterone, estrogen, and estrone .

Vitamin D appears to regulate follicular maturation through a direct effect on anti-Mullerian hormone (AMH) gene, whose product is considered a marker of the
ovarian reserve, via a vitamin D-response element (VDRE) located in the human AMH promoter region . Furthermore, vitamin D promotes the differentiation
and the development of human granulosa cells (GC) . AMH is secreted by the GC of preantral/antral ovarian follicles; however, women with PCOS have
abnormally increased levels of serum and intrafollicular AMH, due to a rise in the number of arrested small antral follicles, besides AMH hypersecretion by the
GC themselves . In a study on GC of the hen, calcitriol significantly decreased the expression of AMH mRNA levels . However, in a study on 54 women who
underwent in vitro fertilization, Merhi et al. found a twofold increase in AMHR-II expression in GC of women with insufficient follicular fluid 25(OH)D (< 30 ng/mL)
compared with women with follicular fluid vitamin D levels > 30 ng/mL . Furthermore, exposure of human GC to vitamin D3 increased progesterone production
in the presence of pregnenolone, suggesting that vitamin D alters AMH signaling and steroidogenesis in human cumulus GC, possibly reflecting a state of GC
luteinization potentiation. . Another in vitro study on human ovarian cells showed that, upon binding to VDR, vitamin D3 increases estrogen, progesterone,
estrone, and insulin-like growth factor-binding protein 1 secretion . Moreover, vitamin D3 acted synergistically with insulin to stimulate estradiol production, and
vitamin D enhanced the inhibitory effect of insulin on IGFBP-1 production .

In vitro, vitamin D is capable of increasing 3β-HSD mRNA levels and progesterone production in the ovarian GC; thus, it may enhance key steroidogenic
enzymes involved in the synthesis of androgens and estrogens . In addition, vitamin D modulates follicular sensitivity to FSH . Although the relationship between
vitamin D and FSH receptor (FSHR) is unclear, there is evidence for a correlation between AMHR-II and FSHR gene expression, with a probable involvement of
vitamin D in the regulation of both AMHR-II and FSHR . Although conflicting, these findings suggest that vitamin D influences AMH gene expression and
probably, it could neutralize the inhibitory effect of AMH on GC differentiation and follicular growth by inhibiting AMHR-II expression and downstream signaling .

In the last few years, it has been debated whether vitamin D is capable of influencing ovarian folliculogenesis, as indicated by the AMH levels and what kind of
relationship exists . Most cross-sectional studies demonstrated a negative correlation between serum levels of AMH and serum levels of vitamin D, but other
studies reported a positive relationship . Such differences could be explained by the heterogeneity in the enrolled populations, the individual vitamin D levels

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and the seasonal variations . Interventional studies revealed that vitamin D supplementation influences AMH serum levels but the effect depends on the
ovulatory status of the women: AMH levels increase in ovulatory non-PCOS women but they decrease in women with PCOS .

Vitamin D and PCOS

Several studies showed that the vitamin D pathway might have a role in the development of various symptoms of PCOS including ovulatory dysfunction with
infertility, insulin resistance (IR), hirsutism, and cardiovascular risk . Upon comparing PCOS with non-PCOS women, serum levels of vitamin D were reported
either lower in the first group or statistically similar . Interventional studies revealed that vitamin D supplementation might improve menstrual irregularity and
follicular development in women with PCOS .

VDR polymorphism and PCOS

There is consistent evidence that polymorphic variants of VDR are associated with low levels of vitamin D in PCOS and pathogenesis of PCOS metabolic
aspects and endocrine symptoms . However, the exact mechanism by which VDR polymorphic variants influence PCOS is unclear . One possibility is that
polymorphic VDR gene variants affect the production of their correspondent mRNA and changes in quantity of the corresponding gene product which, in turn,
could influence the insulin secretor capacity . Polymorphic variants that have been studied include VDR Apa-I , VDR Cdx2 , VDR Bsm1 , VDR Fok1 , and VDR
TaqI . Particularly, some studies found that VDR Apa-I and VDR Bsm1 polymorphisms are associated with an increased risk of PCOS, whereas other studies
indicated TaqI and Cdx2 as the VDR variants with possible relation to both susceptibility and severity of PCOS, including higher IR, fasting insulin, testosterone
levels, body mass index (BMI), and lower vitamin D levels in women with PCOS compared to controls . Cdx2 and FokI variants could be associated with
testosterone levels and infertility, respectively , whereas VDR Bsm1 variant would reduce the risk of vitamin D deficiency . However, because most studies were
conducted in Asia, studies from other geographical areas are awaited .

Vitamin D and advanced glycation end-products in PCOS

Oxidative stress is involved in the pathogenesis of PCOS, and a relationship exists between vitamin D deficiency and oxidative stress . Thus, in mouse models
with PCOS the treatment with combined vitamin D and antioxidant reduces the androgen levels and in the human GC of women with PCOS, vitamin D improves
the steroidogenesis and enzymatic antioxidant activity . Particularly, elevated levels of advanced glycation end-products (AGEs), that are produced
endogenously or absorbed exogenously from modern heat-processed diets, are observed in women with PCOS . AGEs and their antiinflammatory soluble
receptors, sRAGE, are implicated in the pathogenesis of PCOS and its metabolic and reproductive consequences . AGEs accumulate in granulosa and techa
cell layers in women with PCOS and consequent worsening of follicular growth .

Recent studies revealed that women with PCOS have significantly lower follicular fluid sRAGE levels and that there is a significant positive correlation between
sRAGE and 25(OH)D levels, both in women with PCOS and without PCOS . Vitamin D supplementation in women with PCOS induce (a) increased serum
levels of sRAGE permitting to bind circulating AGEs that would otherwise adversely affect ovarian function and (b) decreased AMH levels . Furthermore, vitamin
D could attenuate the AGE-induced ovarian dysfunction .

Vitamin D and parathyroid hormone in PCOS

Vitamin D serum levels are lower in obese people, and calcium metabolism is linked with obesity in women with PCOS . Probably, this obesity-related deficiency
results from (1) sequestration of vitamin D by the subcutaneous adipose tissue and/or (2) shorter exposure to sunlight and subsequently decreased synthesis of
vitamin D, because these women tend to go outdoors less frequently than nonobese women . Because of such vitamin D deficiency, obese individuals have
increased serum levels of parathyroid hormone (PTH) . Furthermore, PTH itself could favor obesity by increasing intracellular calcium concentrations (Ca 2 + )
which, in turn, seem to promote triglycerides (Tg) accumulation and inhibit lipolysis .

PTH concentrations are found to be increased in women with PCOS compared with BMI-matched control individuals . Furthermore, obese (but not overweight)
patients with PCOS exhibit significantly higher PTH concentrations than women with PCOS having normal BMI . Apparently, when the effect of adiposity is not
as strong, such as in overweight patients, PCOS contributes independently to increased PTH serum levels . Studies have also shown a direct correlation
between serum levels of PTH concentrations and serum levels of testosterone, independently of BMI and an inverse relationship between vitamin D levels and
androgen levels . Indeed, it seems that administration of high doses of vitamin D (ergocalciferol 50,000 units weekly or biweekly) for 6 months attenuated
hyperandrogenism in 13 women with chronic anovulation due to PCOS, with two of them becoming pregnant . It is possible that a direct relationship between
PTH and PCOS exists and that the beneficial effects of vitamin D on hyperandrogenemia are mediated by the action of vitamin D on insulin sensitivity .

Vitamin D and insulin resistance in PCOS

Vitamin D deficiency appears to be involved in the development of IR and metabolic dysfunctions in PCOS . Serum 25(OH)D deficiency is negatively correlated
with IR, obesity, BMI, adiposity measures and also non-HDL cholesterol, blood pressure and leptin levels, androgen levels, but positively correlated with HDL
cholesterol . IR and hyperinsulinemia have a central role in the pathogenesis of PCOS regardless of obesity . Reproductively, IR increases hyperandrogenism
through insulin-stimulated ovarian androgen biosynthesis, and diminished sex hormone-binding globulin (SHBG) production . Metabolically, IR is associated
with an increased risk for impaired glucose tolerance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular disease . Indeed, women with PCOS
and vitamin D deficiency have a greater prevalence of dysglycemia compared with PCOS women without vitamin D deficiency .

The exact mechanism that links vitamin D deficiency to IR is unknown . Vitamin D appears to regulate the glyco-insulin homeostasis via direct and indirect
actions, namely: (a) stimulation of insulin release through the expression of VDR and the enzyme 1α-OHase in the pancreatic β-cells; (b) increased
responsiveness of glucose transport to insulin through the binding of the 1,25(OH)D-VDR complex to the vitamin D response element of the insulin receptor at
the tissue level; (c) suppression of the release of proinflammatory cytokines that are believed to mediate IR; and (d) regulation of intracellular and extracellular
ionic calcium levels, which are essential for insulin-mediated actions .

Supplementation with both vitamin D and calcium (often in addition with metformin) appears to reduce IR and serum androgens in vitamin D-deficient women
with PCOS with consequent improvement in hirsutism and menses regularity . A recent review and metaanalysis evaluated the effect of vitamin D
supplementation (alone or with co-supplementation) on IR in a total of 601 patients with PCOS . Supplementation with continuous low doses of vitamin D (<
4000 IU/day) or supplementation with vitamin D as a co-supplement may improve insulin sensitivity reducing the fasting glucose concentration (about 6.3% with

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supplementation of vitamin D and other micronutrients), the mean fasting insulin levels (about 22% in some trials), and HOMA-IR . Particularly, HOMA-IR
decreased significantly in subgroups of patients supplemented with continuous low dose of vitamin D ( P = .001) and daily administration ( P = .002) compared
to nonsupplemented patients whereas less benefit was found in patients supplemented with high dose and weekly intake of vitamin D . However, a more recent
review showed better results after supplementation with high doses of vitamin D (4000 IU), compared with low dose (1000 IU) or placebo, for a period of at least
12 weeks . Also, a recent metaanalysis including 10 randomized controlled trials and comparing the effect of vitamin D supplementation with placebo in vitamin
D-deficient PCOS women, confirmed a significant reduction of fasting glucose levels but no significant effect on fasting insulin concentration and HOMA-IR was
observed . In conclusion, vitamin D replacement may have some beneficial effects on IR .

Vitamin D and hyperandrogenism in PCOS

Patients with PCOS have decreased serum levels of follicle-stimulating hormone (FSH) and increased serum levels of luteinizing hormone (LH), which cause
increased androgen synthesis and subsequent development of IR . IR in PCOS leads to hyperinsulinemia with the consequent enhanced ovarian secretion of
androgens, which itself decreases the secretion of SHBG, with low SHBG levels determining elevated free serum testosterone levels . Hyperinsulinemia and
hyperandrogenemia alter both the growth and maturation of the ovarian follicles, and predispose to β-cell dysfunction . In turn, hyperandrogenemia can lead to
visceral adiposity, adipose tissue dysfunction, insulin-signaling abnormalities, and IR, thus determining a vicious circle . Androgen excess is often accompanied
by a deterioration of insulin sensitivity . Thus, hyperandrogenemia is a principal causal factor of the metabolic dysfunctions observed in PCOS .

Usually, serum DHEAS, testosterone, SHBG, and free androgen index (FAI) are used to evaluate the androgenic profile and vitamin D deficiency that are
associated with abnormalities in these markers . For instance, some studies on women with PCOS have reported inverse associations between serum 25(OH)D
levels and testosterone, DHEAS, FAI, and SHBG . Furthermore, hirsute PCOS women have lower 25(OH)D levels than BMI-matched control women .

Vitamin D supplementation may significantly decrease serum total testosterone, while being ineffective in improving other androgenic markers, such as SHBG
or free testosterone . Beneficial results with significant reduction of serum free testosterone and DHEAS were reported in PCOS women after calcium/vitamin D
supplementation . Vitamin D supplementation could have a benefit in metabolic syndrome related to PCOS . A recent review highlighted that vitamin D
supplementation at high doses (4000 IU) for at least 12 weeks, may improve serum levels of SHBG, FAI, and total testosterone . Randomized placebo-
controlled trials are needed to confirm the beneficial effect of vitamin D on hyperandrogenemia and to evaluate the dose and the duration of vitamin D
supplementation that are capable of improving the androgenic profile . A recent randomized clinical trial reported that, compared with 30 placebo-treated
controls, vitamin D supplementation at 50000 IU/week for 12 weeks in 30 overweight women with PCOS decreased hirsutism score, FAI and increased SHBG
and 25(OH)D levels, with significant changes in ovaries ultrasonography and menstrual cycle regularity .

Vitamin D and serum lipidic profile in PCOS

The effect of vitamin D supplementation on lipid profile was evaluated in some trials, suggesting a positive correlation between vitamin D deficiency and an
unfavorable lipid profile in women with PCOS . Vitamin D appears to reduce cholesterol synthesis by activating the transcription of insulin-induced gene-2
(Insig-2), which downregulates Sterol regulatory element-binding protein (SREBP)-2 and inhibits HMGR activity, this enzyme activity being the rate-limiting step
in cholesterol synthesis . It has been suggested that vitamin D reduces hepatic Tg production or secretion due to the increased calcium intake and increased
clearance of circulating lipoprotein particles by activated lipoprotein lipase (LPL) , with calcium being a known trigger of the folding of LPL into active dimers .
Furthermore, vitamin D also reduces Tg accumulation in differentiated adipocytes and facilitates fatty acid β-oxidation, thereby protecting against excessive fat
mass deposition and associated metabolic disturbances .

However, in literature, contrasting results have been reported with some studies showing an improvement of lipid parameters such as HDL, Tg, total cholesterol,
and VLDL , whereas others showed no beneficial effects . A recent metaanalysis including 520 women with vitamin D-deficient PCOS showed that vitamin D
supplementation had no significant effects on HDL-C, LDL-C, and Tg, whereas it decreased total cholesterol levels significantly both at low doses (< 4000
IU/day) and high doses (≥ 4000 IU/day) . Furthermore, the effect of vitamin D on lipid parameters could be influenced by duration of treatment and the dose.
Concerning duration, conclusions cannot be definitive because for some parameters, such as total cholesterol, 8 weeks of vitamin D supplementation are
sufficient to achieve the goal, while other parameters, such as VLDL, need a more prolonged supplementation . Vitamin D supplementation could be suggested
to patients with PCOS who are at high risk of its deficiency and have an atherogenic lipid profile .

Vitamin D, fertility, and IVF outcome in PCOS

As mentioned above, hyperandrogenism, obesity, and IR are often associated with infertility in women with PCOS . Also, vitamin D deficiency appears to be
associated with infertility, because vitamin D-deficient women have decreased pregnancy rate . Furthermore, it has been suggested that vitamin D levels
influence IVF outcomes through effects mediated by endometrium, seat of VDR . A recent retrospective study on women with PCOS found lower serum vitamin
D levels in the infertile group compared with the fertile group, and within the infertile group, obese women had the lowest vitamin D levels . However, there are
few studies about the relationship between vitamin D and female fertility. Some studies suggest that dietary supplementation with vitamin D or its analog
improves parameters of ovarian folliculogenesis and ovulation , and could ameliorate the endometrium stratus for embryonic implantation in in vitro fertilization
(IVF) setting . Furthermore, women with adequate vitamin D levels are more likely to ovulate compared to those with vitamin D deficiency, and they are also
more likely to achieve a live birth . Moreover, in subfertile women undergoing ovulation induction, vitamin D supplementation increases the ovulation rate .

The deficit of vitamin D is associated with decreased probability of live birth after IVF . Kermak et al. demonstrated the benefit of a 6-week vitamin D
supplementation (enriched in omega-3 fatty acids and olive oil) in both men and women before in vitro fertilization . The benefit was in terms of positive
influence on the developing embryo and morphokinetic markers of embryo quality . A prospective cohort study found that vitamin D deficiency is a significant
predictive parameter for both follicle development and pregnancy in anovulatory infertile women with PCOS who underwent clomiphene citrate stimulation .
Normalization of vitamin D levels in infertile women with PCOS and IR improves IVF outcomes, such as quality of embryos and clinical pregnancy rate . Thus,
maintaining a normal serum vitamin D level in women with PCOS is very important for achieving a successful clinical pregnancy following assisted reproductive
technology .

Conclusions
Vitamin D is a pleiotropic hormone, influencing also the reproductive axis, with its pathway being involved in the pathogenesis of PCOS. Indeed:

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–
the prevalence of vitamin D deficiency is relatively high in patients with PCOS (67%–85%);

–
VDR polymorphic variants are linked with PCOS and its severity phenotypes;

–
an association exists between low vitamin D levels and each of obesity, hyperandrogenism, IR, and other metabolic dysfunctions that are PCOS-related;

–
supplementation of vitamin D in vitamin D-deficient women with PCOS improves menstrual regularity, fertility, BMI, lipidic profile, IR, dysglycemia, and
cardiovascular risk.

Many trials are needed to clarify the role and all possible effects of vitamin D on PCOS parameters. Vitamin D is an orally administered, inexpensive, and
relatively well tolerated vitamin. Considering its many functions, its administration should be measured as a treatment in women with PCOS, obese and
nonobese, in addition to insulin sensitizing agents and antioxidants .

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