Abstract
Vitamin D is a steroid hormone with canonical roles in calcium metabolism and bone modeling. However, in recent years there has been a growing body of literature presenting associations between vitamin D levels and a variety of disease processes, including metabolic disorders such as diabetes and prediabetes and autoimmune conditions such as thyroid disease. This review focuses on the potential role of vitamin D in both male and female reproductive function. The vitamin D receptor (VDR) is expressed throughout central and peripheral organs of reproduction. VDR is often co-localized with its metabolizing enzymes, suggesting the importance of tissue specific modulation of active vitamin D levels. Both animal and human studies in males links vitamin D deficiency with hypogonadism and decreased fertility. In females, there is evidence for its role in polycystic ovary syndrome (PCOS), endometriosis, leiomyomas, in-vitro fertilization, and pregnancy outcomes. Studies evaluating the effects of replacing vitamin D have shown variable results. There remains some concern that the effects of vitamin D on reproduction are not direct, but rather secondary to the accompanying hypocalcemia or estrogen dysregulation.
Vitamin D physiology and metabolism
Vitamin D is an essential steroid hormone classically known for its role in maintenance of calcium and phosphate homeostasis. The name “vitamin D” is a misnomer as the source is not entirely dietary. Vitamin D is largely generated in the epidermis with exposure to ultraviolet radiation. A small percentage of vitamin D (5%) is derived from dietary sources. In areas with less sun exposure, the requirements need to be met by external supplementation and fortified foods. Two different forms of vitamin D from dietary sources are vitamin D2 (ergocalciferol) derived from plants and vitamin D3 (cholecalciferol) derived from animals [1].
The cutaneous precursor of vitamin D, provitamin D3 (7-dehydrocholesterol), is derived from cholesterol in food. After exposure to short wave UVB radiation the B ring of 7-dehydrocholesterol is transformed into previtamin D3 (cholecalciferol) or converted into two inactive products luminosterol and tachysterol. These two products prevent excessive vitamin D production. Vitamin D is transported in blood mostly in a protein bound form. Greater than 80% is bound to vitamin D binding protein (VDBP). It undergoes two hydroxylation steps by P450 mixed function mono-oxidases. In the liver, vitamin D hydroxylation into 25-hydroxyvitamin D (25(OH)D) is modulated by the mitochondrial CYP27A1 or the microsomal CYP2R1. Further hydroxylation takes place in the kidney in the proximal convoluted tubule (PCT) to the physiologically active form, 1 α,25-dihydroxyvitamin D3 (1,25(OH)2D3), by CYP27B1. In target cells, the presence of 1,25(OH)2D3 upregulates the mitochondrial enzyme CYP24A1, which inactivates circulating forms of vitamin D. The expression of these enzymes has now also been documented in a number of peripheral tissues, indicating local regulation of active vitamin D levels [2–4] (Figure 1).
The major source of vitamin D is the skin.
Here the precursor of vitamin D (7-dehydrocholesterol) is transformed into cholecalciferol. A small fraction of active vitamin D precursor is obtained from the intestine. In the liver, mitochondrial CYP27A1 and microsomal CYP2R1 regulate the conversion of vitamin D into 25-hydroxyvitamin D. Bound to vitamin D binding protein (VDBP), it undergoes 1α-hydroxylation by CYP27B1 in the kidney. In target cells, 1,25(OH)2D3 upregulates CYP24A1, which transforms vitamin D into its inactive form.
Active vitamin D binds to VDBP and is transported to target cells. Once the complex reaches the target cell, vitamin D is released from the VDBP and 1,25(OH)2D3 binds to vitamin D receptors (VDR) present in the cytoplasm. VDR transports vitamin D into the nucleus. There it undergoes conformational changes in order to interact with transcriptional factors. The activated VDR joins with retinoid X receptor (RXR) and other co-activators such as the DRIP complex to form a transcriptional regulatory unit that binds to the vitamin D response element (VDRE) in the promoter region of genes. This binding results in regulation of gene expression. [1–3] (Figure 2). In addition to the genomic ligand binding pocket that regulates gene transcription, there is an additional ligand binding pocket on the VDR protein that can mediate more rapid non-genomic effects [5]. These non-genomic effects include rapid increases in intracellular calcium channels, activation of phospholipase C, and opening of calcium channels. The physiological importance of non-genomic actions of vitamin D has not yet been well studied [3].
Once 1,25(OH)2D3 reaches the target cell it binds to the cytoplasmic vitamin D receptor (VDR).
VDR bound 1,25(OH)2D3 is then transported into the nucleus. Here, it complexes with co-activators such as retinoid X receptor (RXR) and the DRIP complex. This transcriptional unit binds to the vitamin D response element (VDRE) in the promoter region of genes, in order to regulate transcription.
Vitamin D deficiency is defined as a serum concentration of 25(OH)D below 20 ng/mL, and vitamin D insufficiency as a 25(OH)D level of 21–29 ng/mL [6]. One third of the population in the US is vitamin D deficient [7]. Forty-two percent of African-American girls and women aged 15–49 years throughout the US have a 25(OH)D level below 15 ng/mL at the end of the winter [8]. Pregnant and lactating women who take a prenatal vitamin and calcium supplements with vitamin D (400 IU/day) remain at high risk for vitamin D deficiency [9]. The 2011 Endocrine Society Clinical Practice Guideline for the evaluation, treatment, and prevention of vitamin D deficiency recommended that pregnant and lactating women require at least 600 IU/day of vitamin D and recognize that 1500–2000 IU/day may be needed to maintain a 25(OH)D level above 30 ng/mL [6].
Classic target actions of vitamin D
The classical actions of vitamin D involve calcium and phosphorus metabolism. There are three major target organs. These are: the intestines, bone, and the parathyroid glands. In the intestines, vitamin D enters the enterocytes and induces synthesis of the intestinal calcium binding protein, calbindin-D9k. Calbindin links with microtubules to facilitate transport of calcium across the enterocyte. Calcium release from the intestine is also dependent on calcitriol-induced expression of the ATP-dependent plasma membrane calcium pump (PMCA1b). In the bone, 1,25(OH)2D3 affects both stimulation of osteoclastogenesis and bone resorption and modification of osteoblast function and bone mineralization [1, 3].
In the parathyroid gland, 1,25(OH)2D3 regulates gene transcription and cell proliferation. VDR null mice showed the importance of classic VDR signaling on PTH expression and regulation of the calcium axis. These mice have growth retardation, rickets and secondary hyperparathyroidism [10]. Treatment with calcium, phosphorus, and lactose normalizes serum calcium and PTH levels. But there remains a profound renal leak of calcium. Pharmacological doses of vitamin D are not able to correct the effects, confirming the absence of vitamin D signaling. This effect also emphasizes the importance of classic VDR signaling in calcium homeostasis functions. In the parathyroid glands, vitamin D does also seem to have a regulatory role in calcium sensing receptor (CaSR) expression [1, 3].
Non-classic roles of vitamin D
In recent years, VDR expression has been confirmed in a variety of tissues, including immune cells, the pancreas, the cardiac system, and skeletal muscle. It is not surprising, then, that fluctuations in vitamin D levels have been correlated with various clinical syndromes [11, 12]. Vitamin D deficiency has been associated with diseases like tuberculosis. In both animal and human studies, autoimmune diseases such as type 1 diabetes, multiple sclerosis, inflammatory bowel disease (IBD), and nephritis have also been linked to vitamin D deficiency [1]. VDR has been identified in cardiac myocytes, fibroblasts and vascular cells, suggesting a potential role in cardiovascular disorders such as hypertension, myocardial hypertrophy, and peripheral vascular disease. Importantly, there is a high prevalence of vitamin D deficiency in type 2 diabetes, prediabetes, and metabolic syndrome. However, treatment with vitamin D has shown variable results [13]. Currently, a large multicenter randomized controlled trial (D2d study) is being conducted to evaluate if vitamin D supplementation decreases progression from prediabetes to diabetes [14]. More recently there has been increased interest in the role of vitamin D in reproductive function [15].
Genetic alterations in vitamin D and reproductive function
Generation of the VDR knock out mouse showed both male and female reproductive dysfunction. Male mice showed decreased sperm count as well as decreased motility. Histological abnormalities of the testis were noted. Female mice presented with uterine hypoplasia and impaired folliculogenesis. Aromatase activity was significantly decreased compared to wildtype mice: by 24% in the ovary, by 58% in the testis, and by 35% in the epididymis. Gene expression of aromatase followed a similar trend [10, 16]. Interestingly, testosterone levels in males remained normal. These mice had elevated LH and FSH levels indicating hypergonadortophic hypogonadism, emphasizing the importance of peripheral gonadal actions of vitamin D. The Leuven Vdr-ablated (Vdr–/–) mice were established as a model of vitamin D-resistant rickets. In this mouse model of inactivated vitamin D signaling, however, testicular histology as well as testosterone and estradiol production was normal. There were changes noted in ERβ and Erα expression in the testes. The significance of these changes to reproductive function has not been fully elucidated. In humans, children with 1,25(OH)2D3 resistant rickets secondary to a lack of VDR showed a normal testosterone response [17].
Vitamin D and male reproduction
Association studies have suggested a link between vitamin D and decreased androgen levels and subfertility in both male animal and human studies. In the rat model, vitamin D deficiency during weaning to maturation resulted in a 45% decrease in successful matings when compared to vitamin D sufficient counterparts. Female rats inseminated by vitamin D deficient males showed a 73% decrease in fertility [18].
In a recent cross-sectional study performed in humans, 2299 men referred for angiography were assessed for 25(OH)D and testosterone levels. Men with 25(OH)D levels above 30 had significantly higher testosterone levels [19]. In a case control study with 122 men with type 2 diabetes, 51 hypogonadal men had a significantly lower 25(OH)D level than 71 men with normal gonadal function, 20.1±6.58 vs. 24.0±5.6 ng/mL, p<0.01 [20]. A Danish publication, however, showed a non-significant trend in lower sperm count and percentage of normal sperm morphology with higher levels of vitamin D [21].
There may be a difference in role for vitamin D in the developing male reproductive system and the adult male reproductive system. In young men and adolescents, concentrations of testosterone and LH were similar in vitamin D replete and deficient groups. However, in older men, positive associations were noted between vitamin D and testosterone levels. VDR is expressed in human gonocytes, immature sertoli cells, and Leydig cells as early as gestational week 16. Interestingly, in human Sertoli cells, VDR is expressed mainly in fetal or immature cells, but in mice they are also seen in mature Sertoli cells. The role of vitamin D in developmental physiology however, remains to be fully elucidated [22]. Other studies have failed to show such an association [18, 23].
Vitamin D in central reproductive organs
In order to further support a role for vitamin D in male reproductive function, a required element is the evidence of its presence and action in target tissues. The male reproductive system is composed of central organs such as the hypothalamus and the pituitary as well peripheral organs such as the testes and the various stages of developing spermatozoa (Figure 3). The pattern of VDR expression in both animal models such as rodents and in the human brain has been noted to be similar. Both VDR and 1 α-hydroxylase expression are seen in neurons and glial cells. The predominant expression, however, is in the hypothalamus and the substantia nigra. Immunohistochemistry has noted the presence of VDR in the nucleus and 1 α-hydroxylase throughout the cytoplasm [24].
Vitamin D receptor (VDR) is localized in both central and peripheral organs of the male and female reproductive tracts.
In the brain it is found in neurons and surrounding glial cells. In the male peripheral reproductive tract it is found in the ducts, sertoli and leydig cells, germ cells, developing spermatozoa and mature sperm. In females, VDR is found throughout the reproductive tract, in the uterus and the ovary. During pregnancy, VDR expression is noted in the placenta.
VDR mRNA and protein expression was confirmed in human pituitary samples, suggesting a role for this hormone in central reproductive organs [25]. The pituitary transcription factor-1 (Pit-1) gene is expressed in the pituitary gland as well as other non-pituitary cells. In the pituitary, the Pit-1 gene is important in the development of the anterior pituitary gland and acts as a transcriptional activator for growth hormone (GH) and prolactin gene expression. Chromatin immunoprecipitation analysis has shown that Pit-1 binds to the VDR promoter. Interestingly this binding also increases recruitment of VDR protein to its own promoter [26]. A second publication has shown that treatment of MCF-7 human breast cancer adenocarcinoma cells with 1,25(OH)2 D3 leads to a decrease in Pit-1 mRNA and protein levels. Gel mobility shift and chromatin immune precipitation assays have shown direct interaction between the vitamin D homodimer and the Pit-1 promoter [27].
Vitamin D in peripheral male reproductive organs
Expression of VDR has now been confirmed in all levels of the male reproductive axis. In the male gonads, both VDR and its metabolizing enzymes are expressed in components of the testes and the reproductive tract: Sertoli cells, germ cells, Leydig cells, spermatozoa, and the epithelial lining of the ducts. This has been demonstrated in animal models such as the rat [28, 29], the mouse [30, 31], rooster [32] and the ram [33]. It has also been shown in a similar distribution in human male reproductive tissues [34]. Biochemical studies have shown that the VDR has high affinity for its ligand in the human testes but low binding capacity [35].
Vitamin D in male mature sperm
The presence of VDR in human sperm was initially described in 2006. Evaluation of sperm from 10 fertile men has shown expression of VDR predominantly in the head and nucleus. There is also some localization in the neck region. The molecular weight of the VDR was noted to be 50 kDa [36]. Nuclear localization was confirmed with electron microscopy studies [37]. Binding to VDR is time and temperature dependent. Labeling studies have demonstrated specificity of binding of 1,25(OH)2D3 to the VDR receptor [35]. Western blot studies have also indicated the presence of the mitochondrial enzyme CYP24A1 within human sperm, suggesting local regulation of 1,25(OH)2D3 concentrations [37]. The vitamin D inactivating enzyme CYP24A1 is regulated by vitamin D. Its expression in human sperm is noted at the annulus. CYP24A1-expressing spermatozoa are lower in subfertile men [38].
In a cross-sectional study evaluating healthy men from the general population, vitamin D deficiency was correlated with reduced sperm motility and percentage of normal morphology [39]. Administration of 1,25(OH)2D3 has been shown to increase sperm motility and acrosin activity suggesting its importance in developing fertilization capacity. It has also been shown to decrease triglyceride content in sperm, perhaps adding to its functional ability [40]. Targeted deletion of 1α-hydroxylase in mice leads to a phenotype of decreased sperm count and mobility in the male 1α(OH)ase(–/–) genotype. These findings were accompanied by down regulation of cyclin E and CDK2 and up-regulation of p53 and p21 expression. However, correction of serum calcium and phosphorus levels in these mice reversed the defective reproductive phenotype [41].
The mature sperm presents an interesting paradigm to study non-genomic actions of vitamin D in conjunction with its receptor. A recent publication showed that VDR activation leads to a rapid increase in AKT, MAPK, GSK3. The authors hypothesized that the initial signal is thus amplified by production of secondary messengers such as inositol triphosphate and diacylglycerol [42]. It is likely that these non-genomic functions of 1,25(OH)2D3 are of lesser significance as treatment of VDR null mutant mice failed to ameliorate the phenotype of these mice. Moreover, rapid non-genomic responses to 1,25(OH)2D3 were altered in osteoblasts from homozygous VDR null mice, implying that VDR is necessary for these actions of vitamin D as well [10].
Vitamin D and testicular peptides
Vitamin D also appears to modulate testicular peptides such as anti-Mullerian hormone (AMH) and Inhibin B. Inhibin B acts to coordinate Sertoli cells and spermatocytes in the adult testes. It is used as an indicator of spermatogenesis. AMH is generally produced in immature Sertoli cells and is believed to be important in the development of the male reproductive tract. A recent report showed a positive association between vitamin D and AMH [42].
Clinical trials with vitamin D supplementation
Randomized clinical trials with vitamin D supplementation are the gold standard for showing whether there is a direct effect on male reproductive function. It appears that there may be an ideal or optimal dose of vitamin D for male fertility. Studies in normal mice with vitamin D deficient diets showed decreased testicular function. However, while replacement with a low dose of vitamin D improved these parameters, higher doses caused a worsening of function [43]. A similar pattern is seen with male sperm. Exposure of normozoospermic samples to low concentrations of vitamin D lead to protein phosphorylation and sperm survival, but higher concentrations failed to show such an effect [36]. There is debate as to which form of vitamin D may serve as the ideal supplementation. One study evaluating vitamin D replacement in men with low testosterone and subclinical hypogonadism, showed that vitamin D25 levels rose more effectively in these men with use of 25 hydroxylated vitamin D (calcidiol) rather than cholecalciferol [44].
Direct versus indirect effect of vitamin D
It remains in debate, however, if vitamin D exerts a direct role on male fertility or an indirect role. An experiment done with vitamin D deficient mice showed that fertility improved with vitamin D replacement (vitamin D or 1,25-dihydroxycholecalciferol). However, fertility was also restored in these mice with a high calcium diet, despite persistent vitamin D deficiency [45]. Moreover, VDR null mice supplemented with calcium have shown partial correction of hypogonadism and increased aromatase activity [16]. As noted above, correction of calcium and phosphate balance in 1α(OH)ase(–/–) mice has led to normalization of reproductive function [41]. It has been shown that exposure to 1,25(OH)2D3 leads to release of intracellular calcium through VDR mediated action [39].
Another possible indirect effect of vitamin D on reproduction may be through the regulation of the estradiol concentration within male reproductive organs. The concentration of estradiol is reported to be 100 times higher in the testes than in circulation, suggesting a potentially important role for estrogen in male reproductive function [23]. As noted above, the leuven VDR null mouse model shows altered ER expression pattern [46]. A second mode of alteration of estrogen levels in testis can be through modulation of the aromatase (CYP19A1) gene, which is responsible for conversion of testosterone to estradiol. A copy of the VDRE is present in the promoter region of the CYP19A1 gene. Moreover, treatment with 1,25(OH)2D3 leads to induction of aromatase expression in immature rat sertoli cells in vitro [23].
Tissue specific modulation of vitamin D levels
Interestingly, enzymes that metabolize vitamin D, such as 1α-hydroxylase (CYP27B1) and the vitamin D inactivating enzyme (CYP24A1) are often co-localized with VDR expression in the male reproductive tract. Moreover, CYP27B1 and 25-hydroxylase (CYP2R1) are expressed at greater levels in the testis in comparison to other tissues. CYP2R1 is expressed in both leydig and germ cells; reduced expression has been reported in testis from men with defective spermatogenesis. CYP2R1 expression is actually higher in the testis than in the liver. Nevertheless, 25 hydroxylation of vitamin D does occur predominantly in the liver, as low circulating levels of 25(OH)D are seen in mice following hepatectomy [23]. The concomitant expression of VDR and its metabolizing enzymes, however, indicate local modulation of vitamin D production that may differ from systemic vitamin D levels.
Several other factors have been implicated as autocrine and paracrine modulators of vitamin D expression: IFNγ, IGF-1, BMPs, TGF-β and 1,25(OH)2D3. FGF23 appears to also have an effect on vitamin D metabolism within the testes. It inhibits 1α-(OH)2D3 production by decreasing CY27B1 and conversely increasing CYP24A1 expression. Interestingly, the Fgf23 null mice do exhibit male infertility. PTHrp is also produced by germ cells. However, its specific effect on vitamin D metabolism is yet to be determined. 1,25(OH)2D3 itself is involved in the feedback downregulation of CYP27B1 and upregulation of CYP24A1 [23, 47].
Vitamin D in germ cell tumors
A final topic in male reproduction is the potential importance of vitamin D in male germ cell differentiation. Although this is not directly related to reproductive function, these tumors do derive from the reproductive tract. Moreover, testicular germ cell tumors are the most frequent type of solid tumor in young men [23]. Both vitamin D and its metabolizing enzymes have a high level of expression in carcinoma in situ but decrease with dedifferentiation to embryonic carcinoma [38]. It is believed that the anti-proliferative effects of vitamin D are mediated through cell cycle regulators such as p21, p27, p63, or p73. Of note, cisplatin is part of the treatment regimen for testicular cancer. In vitro studies have shown decreased need for cisplatin with the concomitant use of 1,25(OH)2D3. This raises the possibility that addition of vitamin D can decrease toxicity from testicular cancer treatment. However, in vivo studies in mouse models have not been able to duplicate this effect [23].
Vitamin D and female reproduction
The female reproductive system, as the male reproductive system, is composed of central regulators including the hypothalamus and the pituitary gland and peripheral organs such as the ovary, uterus, and during pregnancy the placenta. VDR expression has been noted throughout the female reproductive tract (Figure 3) [48]. In the VDR null mice, uterine hypoplasia and defective folliculogenesis have been noted. There was also a decrease in aromatase activity and gene expression. These changes were accompanied by elevated LH and FSH in the females as in the males, suggesting a peripheral defect rather than a central one. Aromatase activity in these mice was increased to 60% of wild type and gonadal function improved with estradiol and calcium supplementation. However, LH and FSH remained elevated indicating persistent impairment of primary gonadal function [48]. In vitro studies have shown a direct modulation by vitamin D of estradiol, estrone, and progesterone production in human ovarian cells [49].
In female reproductive physiology. antimullerian hormone (AMH) is a marker of ovarian reserve. AMH inhibits recruitment of primordial follicles into folliculogenesis [49]. There have been several studies suggesting modulation of AMH levels by vitamin D. A functional VDRE has been noted in the promoter region of the AMH gene [50]. Association studies in humans have shown a positive correlation between vitamin D and AMH levels. One study in HIV positive women with regular menstrual cycles has shown decreased AMH levels with lower vitamin D levels [51]. Another study reported that seasonal changes in AMH levels were correlated with vitamin D status [52]. Supplementation with 1,25(OH)2D3 was able to reverse the seasonal decrease in AMH levels [42]. However, a prospective study evaluating 1,25(OH)2D3 replacement in vitamin D deficient premenopausal women did not show any improvement in AMH levels (p=0.6) [48]. Interestingly, a cross-sectional study evaluating vitamin D levels in 73 healthy female volunteers showed a correlation with testosterone levels but not with markers of ovarian reserve [53].
PCOS
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age. Its manifestations, though varied, include menstrual irregularities, hyperandrogenism, polycystic ovaries, and infertility [54]. Approximately, 67%–85% of women with PCOS have serum concentrations of vitamin D25 <20 ng/mL [55]. Genetic polymorphisms of VDR, in particular the rs757343 single nucleotide polymorphism (SNP) of the VDR gene, have not been associated with increased risk of PCOS, but do correlate with the severity of disease presentation [56]. One study in Tehran, however, did not find any difference in vitamin D levels in women with and without PCOS [57]. Nevertheless, PCOS is a heterogeneous disease. It is plausible that vitamin D plays a role in pathogenesis or presentation in a subset of PCOS patients.
Fifty to seventy percent of women with PCOS have metabolic disturbances, such as insulin resistance. They also have a higher incidence of metabolic syndrome, hypertension, hyperlipidemia, diabetes, and obesity [54]. It is unclear, however, whether vitamin D levels may affect the PCOS reproductive phenotype directly or via their effect on metabolic parameters. While some studies have shown an inverse relationship between vitamin D and androgens such as testosterone and DHEAS [58], most have defined an independent association between vitamin D and metabolic parameters rather than reproductive parameters in women with PCOS.
Vitamin D deficiency in PCOS patients predicts more severe metabolic disturbances, including obesity, homeostatic model assessment-insulin resistance (HOMA-IR), and BMI [58]. In multivariable analyses, vitamin D and BMI were independent predictors of HOMA-IR, quantitative insulin sensitivity index (QUICKI), and metabolic syndrome [59]. In a study population, divided into three groups by vitamin D status, insulin resistance was greatest in the patients with most severe vitamin D deficiency [60].
One study evaluated the effects of vitamin D replacement in 15 women with PCOS. Treatment with a vitamin D3 analog (alphacalcidiol) for 3 months showed an increase in the first phase of insulin secretion, and improvement in lipid profiles [61]. A similarly small study with 11 patients did not show improvement in glucose or insulin levels after three weeks of treatment, but did show a significant decrease in HOMA-IR. Interestingly, androstenedione, total and free testosterone, and DHEAS levels were not altered. However, a longer treatment period may be necessary to detect an improvement in these parameters [62]. A larger study of 46 patients did observe a significant decrease in fasting glucose, stimulated glucose, and C-peptide levels. There was as well a significant decrease in estradiol and triglyceride levels. However, there was no change noted in androgen levels despite improvement in menstrual irregularities in a percentage of the women [63].
There is some interest in the effect of advanced glycation end products (AGEs) and anti-Mullerian hormone (AMH) in the presentation of PCOS. AMH levels are elevated in women with PCOS, suggesting abnormal ovarian folliculogenesis. sRAGE is a soluble receptor for advanced glycation end products (AGEs). In diabetes, AGEs have been implicated in a pro-inflammatory response. The soluble receptor for AGE (sRAGE) binds AGE and prevents its deposition and adverse effects. In animal models, vitamin D supplementation has decreased the deposition of AGEs in the vascular system. One study evaluated the effects of 1,25(OH)2D3 supplementation in women with PCOS (cases with PCOS=22, controls without PCOS=45). In women with PCOS, vitamin D3 increased sRAGE levels (p=0.03) and decreased AMH levels (p<0.001) [62, 64]. A different study looking at seasonal increase in vitamin D levels did not find an effect on circulating AMH levels [65]. This study was performed in South Australia. The patient population studied may reflect a different genetic background than those in the earlier study.
Endometriosis and leiomyoma
The etiologic factors for endometriosis and fibroids are not fully understood. However, vitamin D seems to have the capacity to exert a modulating effect on both of these processes. Vitamin D is said to have anti-immunogenic properties. Inflammation may be important in endometriosis. In animal models, treatment with 1,25(OH)2D3 has shown improvement in endometriosis parameters. In mice, elocalcitol, a selective vitamin D receptor agonist, inhibits lesion development [66]. In the rat, 1,25(OH)2D3 supplementation lowers the size of endometriosis. This is also accompanied by lower levels of VEGF and matrix metalloproteinase-9 [67, 68]. In a prospective study in humans, dairy food intake was associated with a lower risk for endometriosis [69, 70].
Similar associations and efficacy of treatment with vitamin D have been noted with uterine fibroids (UF) and leiomyoma cells. A recent study with cases of self reported uterine leiomyoma showed an increased odds ratio (OR) for association with polymorphisms of the vitamin D receptor after adjustment for age, geographic region, and ethnicity [71]. Other studies have corroborated such associations between vitamin D and both presence and volume of UF. There appeared to be a greater association in black subjects than in Caucasian subjects [72, 73].
Administration of vitamin D has been shown to decrease myometrial and leiomyoma cell proliferation in both in vitro and in vivo models. Growth inhibition in cell lines by 12% has been demonstrated. Moreover, the inhibition was dependent on concentration of vitamin D, with higher levels exerting a greater effect [74]. In vivo, Eker rats with uterine leiomyomas treated with 1,25(OH)2D3 showed significantly reduced leiomyoma tumor size [75].
Investigations into the mechanism by which 1,25(OH)2D3 leads to reduction in leiomyoma cell proliferation have provided several possible downstream candidates. Uterine fibroids have higher metalloproteinase activity than normal myometrium. Treatment of the immortalized human uterine fibroid cell line (HuLM) with 1,25(OH)2D3 reduced mRNA and protein levels of MMP-2 and MMP-9 in a concentration dependent manner [76]. TGF-β3 increases expression of many extracellular matrix proteins that are implicated in tissue fibrosis. HuLM cells treated with TGF-β3 were incubated with and without vitamin D. TFG-β3 induced expression of fibronectin, collagen type 1 protein, and plasminogen activator inhibitor-1 were significantly suppressed with 1,25(OH)2D3 treatment. Phosphorylation of Smad2 and Smad3 were also significantly reduced [77]. 1,25 (OH)2D3 also negatively affects production of cell cycle regulators in HuLM cells such as proliferating cell nuclear antigen (PCNA), BCNA, BCL-2, BCL-w, cyclin dependent kinase (CDK)1, and catechol-O-methyltransferase (COMT) [78].
In-vitro fertilization
Recent data indicate that global rates of infertility have increased from 42.0 million in 1990 to 48.5 million in 2010 [79]. Studies evaluating whether vitamin D plays a role in the success rate of in vitro fertilization procedures have found mixed results. Studies do consistently support a strong correlation between serum and follicular fluid (FF) levels of vitamin D [80, 81]. In one prospective cohort study with 84 infertile women undergoing in vitro fertilization, multivariable regression analysis adjusting for age, body mass index, ethnicity, and number of embryos transferred showed that 25OH-D is an independent predictor of successful implantation and clinical pregnancy [81]. In another study of 101 women, the quality of retrieved embryos was not significantly better in the group with vitamin D sufficiency [80]. The majority of studies, however, failed to detect a significant correlation between vitamin D and outcomes of IVF cycles [82–87]. There may be some ethnic differences in the association of vitamin D and fertility outcomes [88]. A meta-analysis concludes that there is insufficient evidence for vitamin D supplementation in IVF procedures [89]. The importance of the vitamin D status in male donors, however, has not been well studied.
Pregnancy outcomes
Studies presenting the cumulative literature on the potential role of vitamin D in pregnancy outcomes have shown a correlation between vitamin D deficiency and adverse outcomes of pregnancy, such as gestational diabetes, preeclampsia, pre-term birth, low birth weight. A recent meta-analysis of the literature, reviewing 3357 studies showed an increased odds ratio (OR) for gestational diabetes (1.85, 95% CI 1.18–1.89), preeclampsia (1.79, 95% CI 1.25–2.58), and low birth weight (1.85, 95% CI 1.52–2.26) [90–93].
Human studies involving gestational diabetes, support an association between GDM and vitamin D levels as well as its metabolizing enzymes, CYP27B1 and CYP24A1. Both mRNA and protein expression of the metabolizing enzymes were higher in placenta from patients with GDM versus normal pregnancies. VDR expression, however, was not significantly different between the two groups [94]. In a study with 234 women with gestational diabetes and 168 controls patients, only the group with severe vitamin D deficiency showed a significant association. Lower vitamin D levels in the first trimester of pregnancy were not only associated with increased risk for GDM, but also with indices of insulin resistance in the second trimester [95].
Preeclampsia is another complication of pregnancy that is associated with insulin resistance. This condition often results in infants that are small for gestational age (SGA) at birth. Several studies have supported an inverse correlation between vitamin D levels and development of preeclampsia. Vitamin D levels in early pregnancy were lower in women with preeclampsia compared to women without preeclampsia (p<0.01), after adjusted analysis [96]. This association was supported in a study conducted in Canada that evaluated 25(OH)D concentrations at 14 weeks in cases and controls [97]. Serum 25(OH)D levels, later in pregnancy at 24–26 weeks, were also significantly lower in women with preeclampsia than normal controls [98]. In the Collaborative Perinatal Project, vitamin D levels above 50 nmol/L were found initially to have a protective effect on the development of preeclampsia. However, this effect was not sustained after adjusted analyses [99]. An association between vitamin D levels and low SGA has also been noted. Women in the lowest quartile of 25(OH)D level had a higher risk for SGA infants [100]. Other studies have found no relationship between vitamin D and risk of preeclampsia [101–104].
A few studies have evaluated potential downstream modulators of vitamin D action in preeclampsia. In one study, placental growth factor was negatively correlated with preeclampsia. As preeclampsia is a result of endothelial dysfunction, factors such as soluble fms-like tyrosine kinase-1(sFlt-1), placental growth factor (PIGF) intracellular adhesion molecule-1(ICAM-1), and vascular adhesion molecule-1(VCAM-1) may play a role in its pathogenesis. In a prospective cohort study of 697 women, lower vitamin D levels were associated with higher odds of developing preeclampsia. Vitamin D levels showed the strongest positive correlation with PIGF. Vitamin D levels at 12–18 weeks, but not at 24–26 weeks were negatively correlated with ICAM-1. No association was noted with sFLT-1 and VCAM-1. In a recent study, Il-6, a proinflammatory marker with increased expression in metabolic syndrome and diabetes, has been significantly associated with preeclampsia [105]. In this study, vitamin D levels were also correlated with preeclampsia, but no direct measure of association was evaluated between vitamin D and IL-6 in these patients [106].
Randomized controlled clinical trials have evaluated vitamin D supplementation in pregnancy [107]. Safety of daily supplementation with 2000–5000 IU of vitamin D has been established [105]. Clinical trials with vitamin D supplementation in pregnancy have shown conflicting results in terms of birth weight and post-natal growth [108–111]. Several studies have focused on the metabolic outcomes of vitamin D supplementation in pregnancy. A randomized trial with 54 women with GDM showed that vitamin D supplementation leads to a significant decrease in fasting glucose (p<0.001), insulin (p=0.01), and HOMA-IR levels (p<0.001), with a significant increase in the QUICKI index (p=0.003) [112]. A trial in pregnant women with 9 weeks of supplementation with 400 IU of vitamin D versus placebo, showed higher vitamin D levels at the endpoint, but also significantly lower CRP and insulin levels, with significantly higher QUICKI index in the vitamin D treated group than in the placebo group (–1.4 vs. +1.5 μg/mL, p=0.01; –1.0 vs. +2.6 μIU/mL, p=0.04; +0.02 vs. –0.02, p=0.006) [113]. Other studies have not confirmed improvements in metabolic parameters with vitamin D supplementation [114].
The importance of vitamin D in pregnancy may in part result from its function in the gestational uterine decidua, at the maternal-fetal interface. The decidual tissue is formed from the maternal endometrium with invasion of fetal-derived trophoblasts. Close cell to cell interactions facilitate the early stages of fetal-maternal exchange of nutrients and wastes. It is also a source of secretory products such as hormones and growth factors [115]. There is evidence of (1,25(OH)2D3) production in both the maternal and fetal tissues. Both VDR and CYP27B1 expression have been noted in the placenta and the decidua. Moreover, gene expression appears to be induced in pregnancy. Expression of the catabolic enzyme (CYP24A1), however, seems to be decreased in gestation [116–119].
This utero-placental unit is an area where maternal immune function shifts towards tolerance to accept the fetus. The interplay and specificity of subsets of immune cells within the interface are thus important in pregnancy progression. Forty percentage of the decidual stromal population is made of leukocytes: uterine natural killer cells (uNK), macrophages, CD4+ and CD8+ T lymphocytes, and antigen presenting cells (APCs) [116]. Studies have suggested an immunomodulatory role for vitamin D in the placenta. Vitamin D has been correlated with induction of monocyte cathelicidin [115]. Purification of decidual cells shows that adherent cells demonstrate greater 1,25(OH)2D3 levels [120]. Macrophages in the decidua consist of the proinflammatory variety (M1) and anti-inflammatory and pro-tolerogenic variety (M2) of cells. Loss of placental vitamin D, in Vdr and Cyp27b1 gene knockout mice, leads to an exaggeration of pro-inflammatory cells [121]. Furthermore, in vitro studies have shown that 1,25(OH)2D3 inhibits differentiation and maturation of DCs [122]. At the time of implantation, there is a prominence of uNK cells. Numbers of uNK cells have been shown to be altered in preeclampsia. In peripheral blood, 1,25(OH)2D3 inhibits NK activation [114]. uNK cells treated with 1,25(OH)2D3 shows decrease in cytokine production and increase in antimicrobial peptides [123].
Cells of humoral immunity are also noted at the maternal-fetal interface. T cells have been noted to express VDR. Moreover, the expression level of VDR increases with T cell proliferation [124]. Vitamin D seems to promote a shift from Th1 to Th2 cytokine profile [115]. Decidual B cells are low in number during human pregnancy compared to T cells. As with T cells, 1,25(OH)2D3 seems to suppress proliferation and immunoglobulin production [123, 124]. 1,25(OH)2D3 can also inhibit differentiation of plasma cells and class-switched memory cells [125]. A recent study in 183 pregnant women showed that both the peripheral T cell and B cell populations differed depending on vitamin D levels [126–128].
Conclusion
There is now a vast body of literature that supports a role for vitamin D action in both male and female reproductive function. Although VDR expression has been confirmed in both central and peripheral organs of reproduction, the majority of studies indicate a role in modulating gonadal function. The ultimate effect of vitamin D on gonadal function may be direct or indirect via effects on patterns of gene expression. Binding of the VDR complex to VDRE in promoter regions of various genes seems to mediate effects of vitamin D on physiological regulation. It is important to remember that co-localization of vitamin D metabolizing enzymes in peripheral tissues may help to modulate effects of vitamin D on reproductive function.
One additional issue in interpreting the studies presented above is the potential for confounding factors in the relationship between vitamin D and reproduction. Ultimately, it is unclear whether vitamin D itself directly affects gonadal function or whether associated factors, such as hypocalcemia, insulin resistance or estrogen level alterations, play a more direct role in reproductive outcomes. Controlled prospective randomized trials are needed to reach definitive conclusions regarding the role of supplementation with vitamin D in male and female reproduction.
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