{"paper_id":"81dcc841-640c-4902-98b2-bea403d3964e","body_text":"Annals of Agricultural and Environmental Medicine 2016, Vol 23, No 4, 671–676\nwww.aaem.plORIGINAL  ARTICLE\nThe role of vitamin D in reproductive \ndysfunction  in women – a systematic review\nPatrycja Skowrońska1, Ewa Pastuszek1,2, Waldemar Kuczyński3,4, Mariusz Jaszczoł5, Paweł Kuć3,4, \nGrzegorz Jakiel6,7, Izabela Wocławek-Potocka8, Krzysztof Łukaszuk1,2,9\n1 Department of Obstetrics and Gynecological Nursing, Faculty of Health Sciences, Medical University of Gdansk, Poland  \n2 INVICTA Fertility and Reproductive Center, Gdańsk, Poland  \n3 Centre for Reproductive Medicine KRIOBANK, Białystok, Poland  \n4 Medical University of Bialystok, Poland  \n5 Department of Chemical and Process Engineering Chemical Faculty, Gdansk University of Technology, Poland  \n6 INVICTA Fertility and Reproductive Center, Warszawa, Poland  \n7 First Department of Obstetrics and Gynaecology, Medical Center of Postgraduate Education, Warsaw, Poland  \n8 Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Department of Reproductive \nImmunology and Pathology, Olsztyn, Poland  \n9 Department of Gyneacological Endocrinology, Medical University of Warsaw, Warsaw, Poland\nSkowrońska P , Pastuszek E, Kuczyński W, Jaszczoł M, Kuć P , Jakiel G, Wocławek-Potocka I, Łukaszuk K. The role of vitamin D in reproductive \ndysfunction in women – a systematic review. Ann Agric Environ Med. 2016; 23(4): 671–676. doi: 1 0.5604/12321966.1226865\nAbstract\nVitamin D is essential for the proper functioning of the human body. There is also evidence of its strong association with \nfertility problems in women. This review aims to evaluate the relationship between vitamin D and diseases affecting \nwomen’s fertility (polycystic ovarian syndrome (PCOS), uterine leiomyomas and endometriosis), and in vitro fertilization \n(IVF) outcome. A systematic review of the literature was conducted in Scopus and PubMed for relevant English language \npublications since 1989. Vitamin D influences the functioning of the reproductive system in women and has been associated \nwith PCOS, uterine leiomyomas, endometriosis and in vitro fertilization (IVF) outcome. However, further studies on larger \ngroups of patients are needed to establish what role vitamin D plays in the treatment of female infertility.\nKey words\nvitamin D, PCOS, endometriosis, uterine leiomyomas, in vitro fertilization\nINTRODUCTION\nVitamin D is a group of fat-soluble steroids responsible for \nenhancing intestinal absorption of calcium and phosphate, \nwhich is directly related to the maintenance of the normal \nstructure and function of the skeletal system. Vitamin D \ndeficiency is frequently seen together with diabetes, various \nforms of cancer, and autoimmune diseases [1].\nThere are two major forms of vitamin D that have \nfundamental importance: ergocalciferol (vitamin D2) and \ncholecalciferol (vitamin D3) [2]. Both can be produced \nunder ultraviolet B radiation (290–315  nm) and do not \nhave any biological activity. Ergocalciferol is produced in \nplants from ergosterol (ergosta-5,7,22-trien-3β-ol) while \ncholecalciferol is synthesized by the epidermis cell from \n7-dehydrocholesterol (7-DHC) (Fig. 1, 2) [3]. All of the serum \ncholecalciferol and ergocalciferol are bound to vitamin \nD-binding protein (VDBP) and transported to the liver \nwhere enzymatic hydroxylation takes place at C-25 leading \nto 25- hydroxyvitamin D (25-(OH)D) [2]. This reaction is \ncatalyzed by the group of hydroxylases belonging to the \ncytochrome P450 (CYP27A1, CYP3A4 and CYP2R1) [4]. \nThe complex of vitamin 25-(OH)D and VDBP is transported \nfrom the liver to the kidneys (and other tissues) where the \nactive form of vitamin D-1α, 25-(OH)\n2D (1α, 25-(OH)2D2 \nand 1α, 25-(OH) 2D3) is formed due to the action of the \n1α-hydroxylase (CYP27B1). Both biologically active forms \nhave identical properties. The level of vitamin D in serum \nis best reflected by the concentration of 25(OH)D, due to its \nlonger half-life and predominant amount in serum [1, 3].\nMost daily requirement for vitamin D3 is derived from \nbiosynthesis in the skin. Many environmental factors affects \nAddress for correspondence: Patrycja Skowrońska, Department of Obstetrics and \nGynecological Nursing, Faculty of Health Sciences, Medical University of Gdansk, \nDębinki 7, 80-952, Gdańsk, Poland\nE-mail: p.kulwikowska@gumed.edu.pl\nReceived: 10 November 2015; accepted: 20 September 2016\nFigure 1. Synthesis of active form of vitamin D3 (frames: examples of \nforms determinable by LC-MS method)\n\nAnnals of Agricultural and Environmental Medicine 2016, Vol 23, No 4\nPatrycja Skowrońska, Ewa Pastuszek, Waldemar Kuczyński, Mariusz Jaszczoł, Paweł Kuć, Grzegorz Jakie l et al. The role of vitamin D in reproductive dysfunction …\nvitamin D skin production, such as: limited access to sunlight \ncaused by latitude, season, cloudiness or air pollution. \nSkin condition and pigmentation (skin type) are also very \nimportant factors [2]. Skin production of vitamin D, largely \ndependent on environmental factors, is often insufficient to \nensure meeting the daily recommended amount, especially \nin highly industrialized countries. The World Health \nOrganization (WHO) defined ‘vitamin D insufficiency ’ as \nserum level of 25OHD below 20 ng/ml (50  nmol/L) [5]. \nHowever, according to the Endocrine Society Clinical Practice \nGuideline, ‘vitamin D deficiency’ is defined as 25(OH)D \nbelow 20 ng/ml (50 nmol/L), and ‘vitamin D insufficiency’ \nas 25(OH)D of 21–29 ng/ml (52,5–72,5 nmol/L). A sufficient \nlevel of vitamin D is a concentration higher than 30 ng/ml \n(75 nmol/L). The cut-off point of 30 ng/ml (75 nmol/L) is \nassociated with maximal suppression of the parathyroid \nhormone (PTH) and optimal calcium absorption [6].\nBiological activity. The active metabolites of vitamin D \nhave broad and diverse biological functions. Active vitamin \nD is involved through genomic and non-genomic actions. \nIn many tissues, vitamin D binds to the nuclear vitamin D \nreceptor (VDR). The complex then binds to the receptor of \n9-cis retinoic acid (RXR) to form a heterodimer with the \nproperties of the transcription factor (genomic action) [7]. \nVDR controls more than 200 genes which are involved in \nmetabolism, anabolism and resorption of the bones, mineral \nhomeostasis, intestinal calcium transport, and cell cycle \ncontrol [8]. VDR also influences the immune system by \ndirectly modulating T-cell proliferation [9] and activating \nthe genes encoding the antimicrobial peptides with natural \nfeatures of antibiotics [10]. VDR is also a repressor for \ninterleukin reducing risk of some autoimmune diseases, \nsuch as diabetes mellitus (type  1) or rheumatoid arthritis \n[3, 11]. Vitamin D and VDR also affects the reproductive \nsystem (Tab. 1).\nThis review aims to gather studies evaluating the \nrelationship between vitamin D and diseases that affect \nwomen’s fertility.\nPhysiological role of vitamin D in reproduction – \nEndometriosis. Endometriosis is associated with endometrial \nhyperplasia outside the uterine cavity, occurring in 7–15% \nof menstruating women [12]. There are several hypotheses \nconcerning the causes of endometriosis but the mechanisms \nof the disease are still unknown. The proposed mechanisms \ninclude the regression of endometrial cells into the body \n672\nTable 1. Effects of vitamin D on gynaecological disorders including methods used for its determination\nDisorder Conclusion Method Ref.\nEndometriosis\nAssociation of higher VDR (vitamin D receptor) and 1α-hydroxylase expression in \nendometriosis\nAssociation of high 25(OH)D3 level with endometriosis\nAssociation of the level of vitamin D with severity of endometriosis (serum \n25(OH)D3 levels – lower in women with severe endometriosis1α,25-\n(OH)\n2D3levels – no difference)\nAssociation of high 1α,25-(OH) 2D3 level with endometriosis\nAssociation of VDBP (vitamin D-binding protein) polymorphisms (GC*2) with \nendometriosis\nImmunohistochemistry method \n \nchemiluminescence technology\nradioimmunoassay\nradioimmunoassay\ntwo-dimensional difference gel \nelectrophoresis\n[14]\n[16]\n[17]\n[18]\n[21]\nSymptoms of \nPolycystic ovary \nsyndrome\nAssociation of low level of vitamin D and insulin resistance\nAssociation of low level of vitamin D and obesity\nCorrelation between vitamin D and hormone-binding globulin (SHGB)\nCorrelation between vitamin D and the free androgen index (FAI)\nELISA method, LC-MS, radioimmunoassay\nradioimmunoassay\nELISA method, radioimmunoassay \nradioimmunoassay\n[31, 32, 33]\n[39, 40, 41]\n[31, 39]\n[39]\nUterine \nleiomyomas\nVitamin D inhibits growth and induces apoptosis of leiomyoma cells\nAssociation of low serum vitamin D and the increased risk of having \nsymptomatic uterine leiomyomas\nAssociation of 25(OH)D3 with uterine fibroid volume (inverse correlation)\nMolecular biology technique, \nImmunohistochemistry method\nchemiluminescence technology, \nradioimmunoassay\nradioimmunoassay\n[51, 52]\n[55, 59, 60]\n[60]\nIn vitro \nfertilization\nAssociation of high clinical pregnancy rate with high 25(OH)D concentrations\nAssociation of high follicular fluid vitamin D concentrations with low mean score \nof embryo quality\nImmunoassay technique, radioimmunoassay\nelectrochemiluminescence immunoassay\n[68, 69, 70, 71, 72]\n[78]\nFigure 2. Synthesis of active forms of vitamin D2 (frames: examples \nof forms determinable by LC-MS method)\n\nAnnals of Agricultural and Environmental Medicine 2016, Vol 23, No 4\nPatrycja Skowrońska, Ewa Pastuszek, Waldemar Kuczyński, Mariusz Jaszczoł, Paweł Kuć, Grzegorz Jakie l et al. The role of vitamin D in reproductive dysfunction …\ncavity (retrograde menstruation), genetic predisposition, \nimmune disorders, cell metaplasia transport through the \nlymphatic and blood vessels, environmental factors, and \naction of vitamin D [13].\nStudies by Agic et al. showed significantly higher VDR and \n1α-hydroxylase expression in endometriosis specimen than \nin healthy tissues, but without any statistically significant \ndifference in the level of 25(OH)D3 [14]. However, a more \nrecent study showed that genetic polymorphism of VDR was \nnot an important factor in the pathogenesis of endometriosis \n(in Brazilian women) [15].\nData presented by Somigliana et al. showed that women \nsuffering from endometriosis had increased serum level \nof 25(OH)D3, compared to the control group, and this \ndifference was statistically significant. Concentration of \n1α,25-(OH)2D3 was also higher in the endometriosis group \nbut the difference  was not statistically significant. The \nquantitative detection of 25(OH)D3 level was performed using \nchemiluminescence technology, and 1α,25-(OH) 2D3 \nwas measured by radioimmunoassay [16]. The statistical \nsignificance of vitamin D3 was confirmed by further research \nusing radioimmunoassay to determinate the level of 1α,25-\n(OH)\n2D3 and 25(OH)D3. Furthermore, the level of vitamin \nD was found to be dependent on the degree of severity of \nendometriosis [17].\nContradictory findings were shown by Hartwell et al. who \nreported a significantly higher level of 1α,25-(OH) 2D3 in \nwomen with endometriosis, while the level of 25(OH)D3 \nwas comparable in both groups. This study, however, was \nlimited by having a smaller sample [18]. A larger study by \nHarris et al. showed an inverse association between predicted \nplasma levels of 25(OH)D3 and the risk of endometriosis [19].\nAccording to Borkowski et al., the concentration of vitamin \nD binding protein (VDBP) in peritoneal fluid of women with \nendometriosis was lower than in healthy patients, while the \ntendency for VDBP in serum was the opposite. These results \nwere not statistically significant. Measurements of VDBP in \nplasma and peritoneal fluid of women with endometriosis \nand the control group were performed with ELISA method \n[20]. Another study attempting to determine the correlation \nbetween VDBP and endometriosis was performed by Faserl \net al. [21]. They concluded that the concentration of vitamin \nD-binding protein was higher in all endometriosis patients \ncompared with the control group (P<0.02). The authors \nsuggested the possible involvement of polymorphism in \nthe VDBP (GC-2) in the pathogenesis of endometriosis. \nMoreover, Faserl et  al. speculated that the inability to \nsufficiently activate macrophages’ phagocytotic function in \nsubjects carrying the GC-2 polymorphism (more prevalent \nin endometriosis patients) may allow endometriotic tissues \nto implant in the peritoneal cavity [21].\nBiologic mechanisms linking endometriosis and infertility \ninclude distorted pelvic anatomy, altered peritoneal function, \novulatory abnormalities, and impaired implantation [22]. The \nlast mechanism could be related to the fact that the eutopic \nendometrium has reduced expression of biological markers \nof endometrial receptivity, such as αvβ3 integrin, glycodelin \nA, osteopontin, and HOXA10 [23, 24]. 1,25(OH)2D3 has a role \nin implantation likely involving the direct transcriptional \nactivation of HOXA10 gene, which is involved in the \nimplantation process as a potent ανβ3 stimulator and might \nbe a mediate trophoblastendometrial interactions during the \nimplantation process [24].\n1,25(OH)2D3 promotes the shift away from Th1-type \nresponses and favours Th2-type immunity by inhibiting \nthe secretion of IL-12, IL-2, TNF and interferons by T cells, \nmacrophages, and dendritic cells [25, 26].\nIn conclusion, concentrations of various forms of vitamin D \nand VDBP may become promising markers for endometriosis, \nbut their possible dependence on environmental factors, such \nas time of year and type of skin, should also be taken into \nconsideration.\nPolycystic ovary syndrome. PCOS is the most common \nendocrine disorder causing infertility and affecting 5 – 10% \nof reproductive age women [27]. The causes of this disorder \nare unknown, but it has been shown that insulin resistance \nand obesity are related to PCOS [28].\nVitamin D impacts metabolism by affecting insulin \nsecretion [3, 29, 30]. Therefore, the search for an association \nbetween PCOS and vitamin D metabolism appears to be \njustified.\nA large number of observational studies have shown an \nassociation between a low level of 25(OH)D3 and insulin \nresistance [31, 32, 33]. However, the mechanisms remains \nunknown.\nOne theory relies on the regulatory effect of vitamin D \non the intracellular and extracellular calcium level that is \nessential for insulin-mediated intracellular processes, and \nmay have impact on insulin secretion [34, 35, 36]. Another \nhypothesis involves the stimulatory effect of vitamin D on \nthe expression of insulin receptors leading to the increase \nof insulin sensitivity [36, 37]. Finally, vitamin D influences \nthe immune system and can cause a higher inflammatory \nresponse associated with insulin resistance [36, 38, 39].\nMoreover, the association between concentration of \nvitamin D and obesity has also been demonstrated in women \nsuffering from PCOS [39, 40, 41]. This can be a consequence \nof the association between obesity and insulin resistance, \ncorrelated with decreased levels of vitamin D [36, 39, 42, \n43]. On the other hand, low levels of vitamin D in obesity \npatients can be caused by unwillingness of the women to \nexpose their bodies to the sun [36].\nVitamin D deficiency is also related to an imbalance \nin hyperandrogenism markers, such as serum \ndehydroepiandrosterone (DHEAS), total testosterone \n(T), free androgen index (FAI), free testosterone, and sex \nhormone-binding globulin (SHBG) [31, 39, 44, 45, 46].\nHahn et  al. examined a group of 120 women suffering \nfrom PCOS and observed a significant correlation between \n25(OH)D (measured by radioimmunoassay method) and \nSHBG as well as FAI [39]. However, Wehr et al. examined \na group of 206 women with PCOS and measured the levels \nof vitamin 25(OH)D in serum using ELISA method. The \nstudy documented a positive correlation of 25(OH)D with \nSHBG. Neither FAI, T, nor free testosterone showed such \npositive correlation [31]. In a pilot study by Pal at al., 12 \noverweight women with PCOS and vitamin D deficiency were \nsupplemented with high doses of this vitamin and calcium. \nAfter 3 months, the patients’ levels of total testosterone and \nandrostenedione were reduced. However, SHBG and FAI \nand parameters of insulin resistance remained unchanged \n[42]. Other reports suggest that dietary supplementation \nwith vitamin D or its analog improve insulin sensitivity and \nsecretion [47] and the parameters of ovarian folliculogenesis \nand ovulation [48]. In conclusion, the association of vitamin \n673\n\nAnnals of Agricultural and Environmental Medicine 2016, Vol 23, No 4\nPatrycja Skowrońska, Ewa Pastuszek, Waldemar Kuczyński, Mariusz Jaszczoł, Paweł Kuć, Grzegorz Jakie l et al. The role of vitamin D in reproductive dysfunction …\nD concentration with metabolic and endocrine parameters \nin PCOS women makes it a potential marker for that disease \nor a potential drug for metabolic disturbances in women \nwith PCOS [46].\nUterine leiomyomas. Uterine leiomyomas are benign \ntumours of unknown etiology. These types of changes may \noccur due to the transformation of the uterine muscle under \ncertain physiological and pathological conditions [49]. This \ndisease affects mostly women during reproductive age [50]. \nLeiomyomas are often asymptomatic, therefore the number \nof women suffering from this disease is underestimated. \nThe most common clinical symptoms include: excessive \nmenstrual bleeding, dysmenorrhoea and intermenstrual \nbleeding, chronic pelvic pain, and possible impact on \nreproductive capacity (i.e. subfertility, early pregnancy \nloss, and later pregnancy complications) [49]. Vitamin D \ndeficiency is currently thought to be a possible cause of this \ndisease.\nOne of the first studies on cultured human leiomyoma cells \ndemonstrated that vitamin D inhibited growth and induced \napoptosis of these cells [51, 52]. These conclusions were also \nconfirmed in studies on animal model [53]. There was a strong \ncorrelation between low serum levels of vitamin D and having \nsymptomatic uterine leiomyomas [54, 55]. Studies show that \nuterine leiomyomas are more frequent in Afro-American \nwomen than in Caucasian and Hispanic populations [49, 56, \n57]. A possible explanation for such disparity in the statistical \nsignificance may be the naturally lower level of vitamin D in \ndark-skinned patients due to the inefficient synthesis of this \nvitamin under UV radiation [58].\nBaird et  al. compared odds of fibroids for women with \nsufficient and insufficient 25(OH)D levels and found that \nthe former group had 32% lower odds compared with \nthe latter. In their study, vitamin D levels were measured \nby radioimmunoassay. It is interesting to note that the \nassociation was similar for black and white women with \nno evidence of heterogeneity by ethnicity [59]. Sabry et al. \nalso confirmed the association between 25(OH)D deficiency \n(measured by radioimmunoassay) and occurrence of uterine \nleiomyomas in both ethnic groups. Moreover, they observed \nstatistically significant inverse correlation between the level \nof vitamin D and total fibroids mass volume [60]. However, \nwithin the ethnic groups this correlation was statistically \nsignificant only in black patients [60, 61]. On the other hand, a \nstudy by Mitro et al. showed no relationship between 25(OH)\nD and odds of uterine fibroids among all examined women. \nHowever, probabilistic sensitivity analysis performed on \nthe same data suggested that insufficient serum 25(OH)\nD was associated with significantly higher odds of uterine \nleiomyomas in white, but not in black patients [62].\nThe molecular mechanism of vitamin D action on \nleiomyoma was associated with a significant reduction in \nthe effects of transforming growth factor beta 3 (TGF-β3) \ninduced protein expression of collagen type 1, fibronectin, \nand plasminogen activator inhibitor-1 proteins, and the \nphosphorylation of Smad2, as well as nuclear translocation \nof Smad2 and Smad3 [60].\nThe growth of uterine fibroids takes place due to the increase \nin cell proliferation and deposition of the extracellular matrix \n(ECM) [63]. Uterine fibroids contain abnormal deposition \nof extracellular matrix (ECM) components that play an \nimportant role in pathogenesis [64, 65, 66]. Halder et  al. \ndemonstrated that 1,25(OH)2D3 was able to reduce uterine \nfibroid growth by modulating the expression and activity \nof metalloproteinses (MMP-2 and MMP-9), which are \ninvolved in degradation of the ECM. Therefore, it seems that \ndisturbances in degradation of ECM, could be an important \nprerequisite for the development of the fibroids [67].\nThe consistent data on the effects of vitamin D on uterine \nleiomyomas makes it a reasonable marker of this disease and \npotential therapeutic agent for the nonsurgical management \nof uterine fibroids.\nIn vitro  fertilization (IVF) outcomes. Positive effects of \nvitamin D on the effectiveness of IVF treatment have not \nbeen clearly detected. Ozkan et  al. in a study on a group \nof 84 patients found positive correlation between the level \nof vitamin D in serum and follicular fluid and tendency to \nachieve clinical pregnancy (CP) following IVF (increased \nlikelihood of achieving CP by 6%, p=0.030). Moreover, high \nvitamin D level was significantly associated with the improved \nparameters of the controlled ovarian hyperstimulation [68]. \nSimilar correlation between the level of vitamin D in serum \nand tendency to achieve CP following IVF was observed by \nGarbedian et al. [69] and Polyzos et al. [70]. This association \nwas also demonstrated in the recipients of egg donation \n[71]. An interesting result was shown by Rudick et al. who \nobserved that the status of vitamin D (in the serum and \nfollicular fluid) and the achievement of CP is dependent \non patient’s ethnicity (p <0.01). Vitamin D deficiency was \nassociated with lower pregnancy rates in non-Hispanic \nwhites, but not in Asians [72].\nHowever, other studies found that vitamin D deficiency \ndid not play an important role in the outcome of ART [73, \n74, 75, 76, 77]. Unfortunately, there is only a small amount \nof data showing the effects of vitamin D on the quality of \nembryos. Anifandis et al. showed a negative effect of vitamin \nD on the quality of embryos (r=-0.27, p=0.027). They reported \na lower quality of embryos and lower likelihood to achieve \nCP in women who had a sufficient vitamin D status (25(OH)\nD>30 ng/ml in follicular fluid), in comparison with women \nwith insufficient (follicular fluid 25(OH)D 20.1–30 ng/ml) \nor deficient vitamin D status (follicular fluid 25(OH)D \n<20 ng/ml) [36, 78]. However, Rudick et al. did not observe \ncorrelation between vitamin D deficiency and ovarian \nstimulation parameters nor embryo quality, suggesting its \neffect may be mediated through the endometrium [72].\nGiven such contradictory results, there is a need for further \nresearch using reference methods for direct determination \nof the level of vitamin D.\nCONCLUSIONS\nVitamin D is involved in regulating the functions of the \nfemale reproductive system. Vitamin D status has been \nassociated with PCOS, endometriosis, uterine leiomyomas, \nand in vitro fertilization (IVF) outcome. However further \nstudies using reference methods for direct determination of \nthe level of vitamin D are needed to confirm its role in the \ntreatment of female infertility.\n674\n\nAnnals of Agricultural and Environmental Medicine 2016, Vol 23, No 4\nPatrycja Skowrońska, Ewa Pastuszek, Waldemar Kuczyński, Mariusz Jaszczoł, Paweł Kuć, Grzegorz Jakie l et al. 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