sign in sign up
<<
Home , Calcitriol, Vitamin D

European Review for Medical and Pharmacological Sciences 2017; 21: 4243-4251 D in reproduction: the more, the better? An evidence-based critical appraisal

A.S. LAGANÀ1, S.G. VITALE1, H. BAN FRANGEŽ2, E. VRTAČNIK-BOKAL2, R. D’ANNA1

1Unit of Gynecology and Obstetrics, Department of Human Pathology in Adulthood and Childhood “G. Barresi”, University of Messina, Messina, Italy 2Department of Reproduction, University Medical Center Ljubljana, Ljubljana, Slovenia

Abstract. – OBJECTIVE: is a -sol- Introduction uble secosteroid that regulates cal- cium, , and Vitamin D is a fat-soluble secosteroid hormone and plays a pivotal role as antiproliferative and that regulates , magnesium, and phos- immunomodulatory . Considering the phate homeostasis1, and plays a pivotal role as an- different sources of synthesis and dietary intake 2 as well as the pleiotropic actions in extremely di- tiproliferative and immunomodulatory mediator . verse (micro)environments of the body, the sup- Despite the endogenous synthesis, it is possible plementation of this Vitamin should be careful- to supplement Vitamin D with : in particular, ly evaluated taking into account the several path- Vitamin D3 () is mainly contained ways that it regulates. In the current brief review, in sea fish fat and oil, while D2 (ergocal- we aimed to summarize the available evidence ciferol) in plants and . about the topic, in order to suggest the best ev- idence-based supplementation strategy for hu- Vitamin D3 is synthesized in the from man reproduction, avoiding the unuseful (and 7-dehydrocholesterol, following the activity of sometimes hazardous) empiric supplementation. B radiation3. It is metabolized within MATERIALS AND METHODS: Narrative over- the body to the hormonally-active form known as view, synthesizing the findings of literature re- 1,25(OH)2D3 through two steps: cholecalciferol trieved from searches of computerized databases. is hydroxylated to 25-hydroxycholecalciferol by RESULTS: Accumulating evidence from in vi- tro fertilization (IVF) trials suggests that fertil- 25-hydroxylase within the liver; after this first ization rate decreases significantly with increas- , Vitamin D is transported by vi- ing levels of 25OH-D in follicular fluid; in addi- tamin D-binding protein (VDBP) into the blood- tion, Vitamin D levels in the follicular fluid are stream; subsequently, 25-hydroxycholecalciferol negatively correlated to the quality of embryos serves as a substrate for 1 α-hydroxylase (CY- and the higher values of Vitamin D are associ- P27B1), forming the active 1,25(OH)2D3 within ated with lower possibility to achieve pregnan- the kidneys4. cy. Both low and high Vitamin D serum concen- trations decrease not only spermatozoa count, The blood level of 25-hydroxycholecalciferol but their progressive motility as well as increase reflects the amount of Vitamin D ingested with morphological abnormalities. Finally, studies in diet or synthetized in the skin, since hepatic animal models found that severe hypervitamino- 25-hydroxylase regulation by these parameters sis D can reduce the total skeletal calcium store is negligible5. On the contrary, the activity of in embryos and may compromise the postnatal 1-a-hydroxylase in the is tightly regu- survival. CONCLUSIONS: Based on the retrieved data, lated: both and low blood we solicit to be extremely selective in deciding levels of phosphate induce its synthesis and mod- for Vitamin D supplementation, since its excess ulate the production of the active hormone6. may play a detrimental role in fertility. Despite the impressive number of published Key Words: studies, data are not still so robust to clearly elu- Vitamin D, In vitro fertilization, , Infertility, Sex hormone receptors. cidate all the pathways and effects of Vitamin D in human reproduction. Considering the different

Corresponding Author: Antonio Simone Laganà, MD; e-mail: [email protected] 4243 A.S. Laganà, S.G. Vitale, H. Ban Frangež, E. Vrtačnik-Bokal, R. D’Anna sources of synthesis and dietary intake as well as active metabolites27,28. Underlining these elements, the pleiotropic actions in extremely diverse (mi- it was recently shown that VDR expression in both cro)environments of the body, the supplementa- human myometrium and endometrium significantly tion of this Vitamin should be carefully evaluated changes throughout the menstrual cycle, suggest- taking into account the several pathways that it ing a hormonal-dependent regulation29. Further- regulates. Based on these elements, in the current more, recent data showed that Vitamin D is able to brief review we aimed to summarize the available stimulate the production of , , evidence about the topic, in order to suggest the and -like growth factor binding pro- best evidence-based supplementation strategy for tein 1 (IGFBP-1) in cultured human ovarian cells; human reproduction, avoiding the unuseful (and interestingly, Vitamin D and insulin synergistically sometimes hazardous) empiric supplementations. inhibit IGFBP-1 production, although Vitamin D alone stimulates IGFBP-1 production in the same Effects of Vitamin D on Hormonal cells19. These events clearly suggest that a cross-talk and Metabolic Regulation: between hormonal and metabolic pathways occurs. Master and Minions In partial agreement with these data, Vitamin D Form the chemical point of view, was also found to be associated with is similar to steroid , and both these through the modulation of insu- compounds act at nuclear level. In particular, Vi- lin receptor expression30; furthermore, Vitamin D tamin D binds and activates the nuclear Vitamin seems to increase insulin sensitivity31. Probably, D receptor (VDR), which is also a member of the effects on estrogen homeostasis may be caused the steroid// receptor superfamily7. by Vitamin D regulatory mechanism on aromatase Subsequently, VDR forms a heterodimer with expression. Nevertheless, scholars showed that Vi- retinoid-X receptor, binds to hormone response tamin D causes only poor changes on steroidogenic elements on DNA and finally drives a pleiotropic acute regulatory protein (StAR), 3-β-hydroxysteroid cascade of events8-12. Among these events, it is dehydrogenase (3-βHSD) and aromatase mRNA ex- 19 widely accepted that 1,25(OH)2D3 has a key role pression , so the scenario seems very far to reach a 13 in and calcium homeostasis , final shape. 1,25(OH)2D3 seems to increase estrogen although it is also known to modulate cell pro- and progesterone production also in human placen- liferation, differentiation, invasion, and ta22,32. In addition, it has been shown to regulate hu- angiogenesis3,14-17. man chorionic (hCG) expression and In this view, since early 80’s it was demonstrated secretion in cultured syncytiotrophoblasts, and to that both decidua and produce some active stimulate and progesterone secretion from 18 33 Vitamin D metabolites, including 1,25(OH)2D3 . In trophoblasts in a dose-dependent fashion . Last but addition, the presence of 1-α-hydroxylase and VDR not least, Vitamin D can induce the transcription receptors was shown in the ovary (particularly in of HOXA1034 in the endometrium, decidua and granulosa cells)19, endometrium20, pituitary gland21 placenta. HOXA10 is known to play a pivotal role and placenta22, suggesting that Vitamin D can or- in orchestrating embryo implantation35 and the de- chestrate several regulatory pathways in human re- velopment of female tract organogenesis36, together production23,24. 1-α-hydroxylase also seems to play with WNT/β-catenin37. Interestingly, treatment with a pivotal role for acrosome reaction in spermatozoa, Vitamin D increases mRNA and protein expression in a paracrine/autocrine fashion, allowing the in- of HOXA1034. In the placental microenvironment, crease of intracellular concentration of Ca+2 ions VDR modulates the transfer of calcium between 25 driven by 1,25(OH)2D3 . Interestingly, the influence trophoblast and the endometrial decidua, helping of Vitamin D on human reproduction seems to be to avoid uterine contraction and, subsequently, re- tightly connected not only to calcium homeostasis, duces the risk of preterm delivery38. The presence but also to its paramount importance as direct reg- of VDR was also demonstrated in and 39 ulator of the aromatase : indeed, spermatozoa . In particular, 1,25(OH)2D3 is able accumulating evidence suggests that VDR-bound to increase intracellular Ca+2 concentration and the

1,25(OH)2D3 acts as a to regulate activity of acrosin in spermatozoa in an autocrine/ the expression of the CYP19 gene, which is widely paracrine fashion25, accounting for the essential ac- known to encode aromatase, the key for rosome reactions during fertilization of the oocyte. 26 estrogen production . In addition, 1,25(OH)2D3 in- Corroborating the hypothesis of autocrine/paracrine duces the production of Vitamin D-24-hydroxylase activity, it was found that CYP27B1, which is

(CYP24A1), which catalyzes its conversion to in- necessary to form active 1,25(OH)2D3, is directly

4244 Vitamin D and reproduction expressed in human male reproductive tract40,41. In significantly with increasing levels of 25OH-D in addition, Vitamin D has been shown to stimulate the follicular fluid; on the other hand, the implan- calcium uptake through a activity tation rate did not significantly increase in the in Sertoli cells42, whose secretory activities are ion same cohort65. Considering that level of 25OH-D channel-dependent. Despite accumulating evidence in follicular fluid is reflective of body stores of already suggested a clear role for 1,25(OH)2D3 and Vitamin D, this evidence suggests that Vitamin VDR in the abovementioned pathways, the risk D deficiency does not play a pivotal role in the of adverse effects of Vitamin D supplementation outcome of IVF and, furthermore, that 25OH-D is still surrounded by lights and shadows. In this level in follicular fluid could not be used as an regards, new data tried to shed light on this “grey independent predictor of clinical . zone”. In particular, it was shown that transcription- In partial confirmation of these results, it was al and translational regulation of progesterone bio- found that Vitamin D levels in the follicular fluid synthesis-related genes in porcine granulosa cells is are negatively correlated to the quality of embry- significantly altered by 1,25(OH)2D3; in addition, the os and that higher values of Vitamin D are associ- same study43 found that progesterone concentration ated with lower possibility to achieve pregnancy; was decreased in response to 1,25(OH)2D3. Proges- in addition, women with overt terone is an essential hormone in reproduction44,45, D had poor IVF outcomes66. Notably, in the same and it has been successfully used as prophylaxis in work, higher levels of Vitamin D corresponded the prevention of spontaneous miscarriage46-49 and with lower levels of glucose in follicular fluid, preterm labour50 thanks to its immunomodulatory corroborating the cross-link between Vitamin properties at the maternal-fetal interface51. Consid- D and glucose metabolism (as previously men- ering these elements, it is possible to hypothesize tioned). In this abnormal condition, altered glu- that Vitamin D excess may cause a reduction of this cose concentration in the follicular fluid may be important hormone and consequently play a severe detrimental for oocyte maturation and growth detrimental role during early pregnancy. of granulosa and cumulus cells, affecting di- It was found that in vitro treatment rectly the oocyte competence67. Furthermore, in human cancer cell line up-regulated 1,25(OH)2D3 seems to alter AMH sensitivity in Anti-Müllerian Hormone (AMH) mRNA ex- granulosa cells obtained from women who un- pression levels52 and that functional Vitamin derwent oocyte retrieval for IVF: according to a D response element (VDRE) was found in the recent data analysis, cumulus granulosa cells cul- 53 promoter region of human AMH gene . Never- tured with 1,25(OH)2D3 show a drastic and signif- theless, recent evidence from large and well-de- icant decrease (32%) in AMH Receptor-II mRNA signed human-based cross-sectional analysis levels68. These data are in partial agreement with clearly demonstrates that Vitamin D deficiency previous researches that showed how Vitamin is highly unlikely to have a detrimental effect on D down-regulated AMH gene and up-regulated ovarian reserve54. Last but not least, the expres- follicle-stimulating gene ex- sion of the parathyroid hormone-related protein pression in hen’s ovaries69,70. Probably, a strong 55-62 (PTH-rP) gene is repressed by 1,25(OH)2D3 ; confounding factor which may play a detrimental considering that PTH-rP has a potent vasore- role in data interpretation about this point is body laxant activity in human endometrium63,64, its mass index (BMI). Although it is widely accepted reduction caused by Vitamin D supplementation that higher BMI is an independent risk factor for may consequently alter the necessary remod- infertility, it was also recently found that the body eling of spiral artery and the correct placental weight of the women with follicular fluid 25(OH) vascular framework development during early D deficiency measured in single follicles was pregnancy. In the following section we try to significantly higher, regardless of the etiology of analyze the reflection of these strong pieces of infertility71. Nevertheless, the literature overview evidence on the clinical practice. about this point is still controversial: as example, others advocated a beneficial role of replete follic- Clinical Evidence about Vitamin D in ular Vitamin D levels for IVF outcomes72. These Reproduction: a Critical Appraisal apparently contradictory results may depend (at The most important data about Vitamin D lev- least in part) not only on Vitamin D concentra- els and human reproduction came from in vitro tion in follicular fluid, but also on the expression fertilization (IVF) trials. In particular, on one of VDBP. Corroborating this hypothesis, it was hand it was shown that fertilization rate decreases found that decreased expression of VDBP in

4245 A.S. Laganà, S.G. Vitale, H. Ban Frangež, E. Vrtačnik-Bokal, R. D’Anna the follicular fluid is associated with improved oncological conditions, including endometrial81,82, IVF outcomes73. In addition, Firouzabadi et al74 ovarian28, breast83,84 and other85-88 . Apart showed that Vitamin D levels in the follicular from female fertility, the probability of a neg- fluid were comparable in the pregnant as well ative effect of Vitamin D also on male fertility non-pregnant women. This element suggests at was suggested after a discovery of a molecular least two key points: first of all, the poor efficacy similarity of VDBP to antisperm antibodies89. In of follicular fluid Vitamin D levels in predicting addition, several studies90-92 found that both low the pregnancy rate during IVF program; second, (<50 nmol/L) and high (>125 nmol/L) Vitamin D the dosage of Vitamin D before IVF program serum concentrations decrease not only sperma- could be considered outdated, since the follic- tozoa count but also their progressive movement ular fluid concentration is a reliable mirror of as well as increase morphological abnormalities, the whole body store of Vitamin D. Moreover, even after adjustment for age, season, BMI, alco- Vitamin D reserve is higher in women with en- hol intake, and smoking. If excess of Vitamin D dometriosis, a condition characterized in most of can be considered a serious danger for both male the cases by infertility75. Notably, a retrospective and female fertility, hypervitaminosis D seems cohort study of 188 infertile women undergoing to be equally dangerous also after conception: IVF showed a positive correlation between se- evidence from animal model suggests that the rum 25OH-D levels and IVF success rate among embryo is not protected against maternal hy- non-Hispanic white women; nevertheless, an op- pervitaminosis D, but rather that 1,25(OH)2D3 is posite correlation was seen among Asian women, transferred through the placental barrier where it where pregnancy rates were higher in those with reduces the total skeletal calcium store in embry- lower serum 25OH-D levels76, confirming that os and may compromise postnatal survival93-95. serum concentration of Vitamin D is not reliable and robust to predict IVF outcomes. Considered altogether, the available evidence allows us to Conclusions hypothesize that a correlation between the serum/ follicular Vitamin D level and the pregnancy rate To date, there are not specific guidelines re- in IVF cycle does not occur. Probably, the real garding Vitamin D supplementation for women field in which the game is played should not be affected by endocrine disturbances and infertil- considered the ovary, but the endometrium77: ity. Our literature analysis leads us to solicit the some authors found that Vitamin D deficiency was necessity to be extremely selective in deciding not associated with the number of follicles and for its supplementation, according to patient’s oocytes or with the morphology of the embryo in condition. In particular, comorbidities96-99 and/or IVF procedures and, furthermore, that Vitamin D specific period of life100,101 which may influence deficiency and insufficiency was associated with the response to Vitamin D should carefully be lower pregnancy rates in recipients of egg dona- evaluated, especially considering the effects on tion78. Adding these two pieces of evidence to the immune system102,103. In addition, the “empiric” puzzle, it is possible to hypothesize that Vitamin supplementation of Vitamin D in healthy women D at physiologic levels has a beneficial role only seems not to be evidence-based and, probably, on endometrial receptivity79, but conversely an may play detrimental effects on fertility104,105. excess of this Vitamin plays a detrimental role in Confounding and opposite results have been ob- the ovarian homeostasis, disturbing the oocytes tained so far from IVF clinical studies: an overall development and consequently embryo quality. analysis allows us to speculate that Vitamin D From the molecular point of view, it is possible at physiologic levels has a beneficial role on en- that the observed effects in clinical practice may dometrial receptivity, whereas an excess of this derive from the Vitamin D action on hormon- molecule plays a detrimental role on oocytes al homeostasis. Indeed, 1,25(OH)2D3 can reduce development and embryo quality, probably due significantly estrogen receptor (ER)-α, progester- to its anti-estrogenic effect (i.e. Vitamin D is able one receptor (PR)-A and –B and steroid receptor to reduce significantly ER-α, PR-A and —B and coactivator (SRC) expression in human uterine SRC expression in human uterine leiomyoma leiomyoma cells80, suggesting a clear role of this cells). According to this element, Vitamin D sup- Vitamin as antagonist of sex plementation should be administered in selected receptors. This antagonistic effect on sex steroid populations and during specific moments of the hormone receptors was also confirmed in several ovarian cycle, in order to support specifically the

4246 Vitamin D and reproduction luteal phase. Finally, Vitamin D should be sup- 12) Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, plemented at appropriate dosage and, according Schütz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM to the most updated recommendations106, only if . The nuclear receptor superfamily: the second decade. Cell 1995; 83: serum concentration falls below 50 ng/ml (equiv- 835-839. alent to 125 nmol/L). 13) Lerchbaum E, Obermayer-Pietsch B. Vitamin D and fertility: a systematic review. Eur J Endocrinol 2012; 166: 765-778. Declaration of Interest 14) Schwartz GG, Wang MH, Zhang M, Singh RK, Siegal All authors have no proprietary, financial, profes- GP. 1 alpha,25-Dihydroxyvitamin D (calcitriol) in- sional, or other personal interest of any nature in any hibits the invasiveness of human product, service, or company. The authors alone are cells. Cancer Epidemiol Biomarkers Prev 1997; 6: responsible for the content and writing of the paper. 727-732. 15) Schwartz GG, Selzer MG, Burnstein KL, Zhuang SH, Block NL, Binderup L. Inhibition of prostate cancer metastasis in vivo: a comparison of 1,23-dihy- droxyvitamin D (calcitriol) and EB1089. Cancer References Epidemiol Biomarkers Prev 1999; 8: 241-248. 16) Mantell DJ, Owens PE, Bundred NJ, Mawer EB, Can- Holick MF 1) . High prevalence of vitamin D inade- field AE. 1 alpha,25-dihydroxyvitamin D(3) inhibits quacy and implications for health. Mayo Clin Proc angiogenesis in vitro and in vivo. Circ Res 2000; 2006; 81: 353-373. 87: 214-220. McDonnell DP, Mangelsdorf DJ, Pike JW, Haussler 2) 17) Ylikomi T, Laaksi I, Lou YR, Martikainen P, Miettinen MR, O’Malley BW. Molecular cloning of comple- S, Pennanen P, Purmonen S, Syvälä H, Vienonen A, mentary DNA encoding the avian receptor for Tuohimaa P. Antiproliferative action of vitamin D. vitamin D. Science 1987; 235: 1214-1217. Vitam Horm 2002; 64: 357-406. Wolf G. 3) The discovery of vitamin D: the contri- 18) Weisman Y, Harell A, Edelstein S, David M, Spirer Z, bution of . J Nutr 2004; 134: 1299- Golander A. 1 alpha, 25-Dihydroxyvitamin D3 and 1302. 24,25-dihydroxyvitamin D3 in vitro synthesis by 4) Prosser DE, Jones G. involved in the human decidua and placenta. Nature 1979; 281: activation and inactivation of vitamin D. Trends 317-319. Biochem Sci 2004; 29: 664-673. 19) Parikh G, Varadinova M, Suwandhi P, Araki T, Ros- 5) Henry HL. Regulation of vitamin D metabolism. enwaks Z, Poretsky L, Seto-Young D. Vitamin D Best Pract Res Clin Endocrinol Metab 2011; 25: regulates steroidogenesis and insulin-like growth 531-541. factor binding protein-1 (IGFBP-1) production in 6) Norman AW, Henry H. The role of the kidney and human ovarian cells. Horm Metab Res 2010; 42: vitamin D metabolism in health and disease. Clin 754-757. Orthop Relat Res 1974; 98: 258-287. 20) Viganò P, Lattuada D, Mangioni S, Ermellino L, Vi- gnali M, Caporizzo E, Panina-Bordignon P, Besozzi 7) Malloy PJ, Tasic V, Taha D, Tütüncüler F, Ying GS, Yin M, Di Blasio AM LK, Wang J, Feldman D. muta- . Cycling and early pregnant tions in patients with hereditary 1,25-dihydroxyvi- endometrium as a site of regulated expression of tamin D-resistant . Mol Genet Metab 2014; the vitamin D system. J Mol Endocrinol 2006; 36: 111: 33-40. 415-424. Pérez-Fernandez R, Alonso M, Segura C, Muñoz I, 8) Christakos S, Dhawan P, Verstuyf A, Verlinden L, Car- 21) García-Caballero T, Diguez C. meliet G. Vitamin D: metabolism, molecular mech- Vitamin D receptor anism of action, and pleiotropic effects. Physiol gene expression in human pituitary gland. Life Rev. 2016; 96: 365-408. Sci 1997; 60: 35-42. Evans KN, Nguyen L, Chan J, Innes BA, Bulmer JN, 9) Adorini L, Daniel KC, Penna G. Vitamin D receptor 22) Kilby MD, Hewison M. agonists, cancer and the : an in- Effects of 25-hydroxyvita- tricate relationship. Curr Top Med Chem 2006; 6: min D3 and 1,25-dihydroxyvitamin D3 on cyto- 1297-1301. kine production by human decidual cells. Biol Reprod 2006; 75: 816-822. 10) Colonese F, Laganà AS, Colonese E, Sofo V, Salmeri Luk J, Torrealday S, Neal Perry G, Pal L FM, Granese R, Triolo O. The pleiotropic effects of 23) . Relevance vitamin D in gynaecological and obstetric diseas- of vitamin D in reproduction. Hum Reprod 2012; es: an overview on a hot topic. Biomed Res Int 27: 3015-3027. 2015; 2015: 986281. 24) Johnson LE, DeLuca HF. Vitamin D receptor null 11) Ross TK, Moss VE, Prahl JM, DeLuca HF. A nuclear mutant mice fed high levels of calcium are fertile. protein essential for binding of rat 1,25-dihy- J Nutr 2001; 131: 1787-1791. droxyvitamin D3 receptor to its response ele- 25) Aquila S, Guido C, Middea E, Perrotta I, Bruno ments. Proc Natl Acad Sci U S A 1992; 89: 256- R, Pellegrino M, Andò S. Human male gamete 260. : 1alpha, 25-dihydroxyvitamin D3

4247 A.S. Laganà, S.G. Vitale, H. Ban Frangež, E. Vrtačnik-Bokal, R. D’Anna

(1,25(OH)2D3) regulates different aspects of hu- 39) Habib FK, Maddy SQ, Gelly KJ. Characterisation man sperm biology and metabolism. Reprod Biol of receptors for 1,25-dihydroxyvitamin D3 in the Endocrinol 2009; 7: 140. human testis. J Steroid Biochem 1990; 35: 195- 26) Kinuta K, Tanaka H, Moriwake T, Aya K, Kato S, Seino 199. Y. Vitamin D is an important factor in estrogen 40) Corbett ST, Hill O, Nangia AK. Vitamin D receptor biosynthesis of both female and male . found in human sperm. Urology 2006; 68: 1345- Endocrinology 2000; 141: 1317-1324. 1349. 27) Jones G, Prosser DE, Kaufmann M. 25-Hydroxyvi- 41) Blomberg Jensen M, Nielsen JE, Jørgensen A, Ra- tamin D-24-hydroxylase (CYP24A1): Its important jpert-De Meyts E, Kristensen DM, Jørgensen N, Ska- role in the degradation of vitamin D. Arch Bio- kkebaek NE, Juul A, Leffers H. Vitamin D receptor chem Biophys 2012; 523: 9-18. and vitamin D metabolizing enzymes are ex- 28) Rodriguez GC, Turbov J, Rosales R, Yoo J, Hunn pressed in the human male reproductive tract. J, Zappia KJ, Lund K, Barry CP, Rodriguez IV, Pike Hum Reprod 2010; 25: 1303-1311. JW, Conrads TP, Darcy KM, Maxwell GL, Hamilton 42) Hamden K, Carreau S, Jamoussi K, Ayadi F, Garmazi F, CA, Syed V, Thaete LG. Progestins inhibit calcitri- Mezgenni N, Elfeki A. Inhibitory effects of 1alpha, ol-induced CYP24A1 and synergistically inhibit 25dihydroxyvitamin D3 and Ajuga iva extract on cell viability: an opportunity for oxidative stress, and hypo-fertility in dia- chemoprevention. Gynecol Oncol 2016; 143: 159- betic rat testes. J Physiol Biochem 2008; 64: 231- 167. 239. 29) Vienonen A, Miettinen S, Bläuer M, Martikainen PM, 43) Hong SH, Lee JE, Kim HS, Jung YJ, Hwang D, Lee Tomás E, Heinonen PK, Ylikomi T. Expression of JH, Yang SY, Kim SC, Cho SK, An BS. Effect of nuclear receptors and cofactors in human endo- vitamin D3 on production of progesterone in metrium and myometrium. J Soc Gynecol Investig porcine granulosa cells by regulation of ste- 2004; 11: 104-112. roidogenic enzymes. J Biomed Res 2016; 30: 30) Heaney RP. Vitamin D in Health and Disease. Clin 203-208. J Am Soc Nephrol 2008; 3: 1535-1541. 44) Di Renzo GC, Giardina I, Clerici G, Mattei A, Alajmi AH, Gerli S. 31) Teegarden D, Donkin SS. Vitamin D: emerging new The role of progesterone in maternal roles in insulin sensitivity. Nutr Res Rev 2009; and fetal medicine. Gynecol Endocrinol 2012; 28: 22: 82-92. 925-932. Di Renzo GC, Mattei A, Gojnic M, Gerli S. 32) Barrera D, Avila E, Hernández G, Halhali A, Biruete 45) Proges- B, Larrea F, Díaz L. Estradiol and progesterone terone and pregnancy. Curr Opin Obstet Gynecol synthesis in human placenta is stimulated by 2005; 17: 598-600. calcitriol. J Steroid Biochem Mol Biol 2007; 103: 46) Haas DM, Ramsey PS. for preventing 529-532. miscarriage. Cochrane database Syst Rev 2013; 33) Avila E, Hernández G, Méndez I, González L, Halh- 10: CD003511. ali A, Larrea F, Morales A, Díaz L. Calcitriol affects 47) Tibbetts TA, Conneely OM, O’Malley BW. Progester- hCG gene transcription in cultured human syncy- one via its receptor antagonizes the pro-inflam- tiotrophoblasts. Reprod Biol Endocrinol 2008; 6: 3. matory activity of estrogen in the mouse uterus. 34) Du H, Daftary GS, Lalwani SI, Taylor HS. Direct Biol Reprod 1999; 60: 1158-1165. regulation of HOXA10 by 1,25-(OH)2D3 in human 48) Carp HJ. in the prevention of mis- myelomonocytic cells and human endometrial carriage. Horm Mol Biol Clin Investig 2016; 27: stromal cells. Mol Endocrinol 2005; 19: 2222- 55-62. 2233. 49) van der Linden M, Buckingham K, Farquhar C, Kremer 35) Bagot CN, Troy PJ, Taylor HS. Alteration of ma- JAM, Metwally M. Luteal phase support for assist- ternal Hoxa10 expression by in vivo gene trans- ed reproduction cycles. Cochrane database Syst fection affects implantation. Gene Ther 2000; 7: Rev 2015; 7: CD009154. 1378-1384. 50) Di Renzo GC, Rosati A, Mattei A, Gojnic M, Gerli 36) Taylor HS, Vanden Heuvel GB, Igarashi P. A con- S. The changing role of progesterone in preterm served Hox axis in the mouse and human fe- labour. BJOG 2005; 112 Suppl 1: 57-60. male reproductive system: late establishment and 51) Bhurke AS, Bagchi IC, Bagchi MK. Progester- persistent adult expression of the Hoxa cluster one-regulated endometrial factors controlling im- genes. Biol Reprod 1997; 57: 1338-1345. plantation. Am J Reprod Immunol 2016; 75: 237- 37) Laganà AS, Sturlese E, Retto G, Sofo V, Triolo O. 245. Interplay between misplaced müllerian-derived 52) Krishnan AV, Moreno J, Nonn L, Malloy P, Swami stem cells and peritoneal immune dysregulation S, Peng L, Peehl DM, Feldman D. Novel pathways in the pathogenesis of endometriosis. Obstet Gy- that contribute to the anti-proliferative and che- necol Int 2013; 2013: 527041. mopreventive activities of calcitriol in prostate 38) Belkacemi L, Gariépy G, Mounier C, Simoneau L, La- cancer. J Steroid Biochem Mol Biol 2007; 103: fond J. Expression of -D28k (CaBP28k) 694-702. in trophoblasts from human term placenta. Biol 53) Malloy PJ, Peng L, Wang J, Feldman D. Interac- Reprod 2003; 68: 1943-1950. tion of the vitamin D receptor with a vitamin

4248 Vitamin D and reproduction

D response element in the Mullerian-inhibiting 64) Casey ML, Mibe M, MacDonald PC. Regulation substance (MIS) promoter: regulation of MIS ex- of parathyroid hormone-related protein gene ex- pression by calcitriol in prostate cancer cells. pression in human endometrial stromal cells in Endocrinology 2009; 150: 1580-1587. culture. J Clin Endocrinol Metab 1993; 77: 188- 54) Drakopoulos P, van de Vijver A, Schutyser V, Mi- 194. latovic S, Anckaert E, Schiettecatte J, Blockeel C, 65) Aleyasin A, Hosseini MA, Mahdavi A, Safdarian L, Fal- Camus M, Tournaye H, Polyzos NP. The effect of se- lahi P, Mohajeri MR, Abbasi M, Esfahani F. Predictive rum vitamin D levels on ovarian reserve markers: value of the level of vitamin D in follicular fluid on a prospective cross-sectional study. Hum Reprod the outcome of assisted reproductive technology. 2017; 32: 208-214. Eur J Obstet Gynecol Reprod Biol 2011; 159: 132- 55) Kajitani T, Tamamori-Adachi M, Okinaga H, Chika- 137. mori M, Iizuka M, Okazaki T. Negative regulation 66) Anifandis GM, Dafopoulos K, Messini CI, Chalvatzas N, of parathyroid hormone-related protein expres- Liakos N, Pournaras S, Messinis IE. Prognostic value of sion by steroid hormones. Biochem Biophys Res follicular fluid 25-OH vitamin D and glucose levels in Commun 2011; 407: 472-478. the IVF outcome. Reprod Biol Endocrinol 2010; 8: 91. 56) Endo K, Ichikawa F, Uchiyama Y, Katsumata K, Oh- 67) Gu L, Liu H, Gu X, Boots C, Moley KH, Wang Q. kawa H, Kumaki K, Ogata E, Ikeda K. Evidence for Metabolic control of oocyte development: linking the uptake of a vitamin D analogue (OCT) by a maternal and reproductive outcomes. human carcinoma and its effect of suppressing Cell Mol Life Sci 2015; 72: 251-271. the transcription of parathyroid hormone-related 68) Merhi Z, Doswell A, Krebs K, Cipolla M. Vitamin D gene in vivo. J Biol Chem 1994; 269: alters genes involved in follicular development and 32693-32699. steroidogenesis in human cumulus granulosa cells. 57) Falzon M. DNA sequences in the rat parathyroid J Clin Endocrinol Metab 2014; 99: E1137-1145. hormone-related peptide gene responsible for 69) Johnson PA, Kent TR, Urick ME, Giles JR. Expres- 1,25-dihydroxyvitamin D3-mediated transcrip- sion and regulation of anti-mullerian hormone in tional repression. Mol Endocrinol 1996; 10: 672- an oviparous species, the hen. Biol Reprod 2008; 681. 78: 13-19. Ikeda K, Lu C, Weir EC, Mangin M, Broadus AE 58) . 70) Wojtusik J, Johnson PA. Vitamin D regulates an- Transcriptional regulation of the parathyroid hor- ti-Mullerian hormone expression in granulosa mone-related peptide gene by cells of the hen. Biol Reprod 2012; 86: 91. and vitamin D in a human C-cell line. J Biol Chem Deriquehem VA, Antunes RA, Reginatto MW, Mancebo 1989; 264: 15743-15746. 71) AC, Areas P, Bloise E, Souza Mdo C, Ortiga-Carvalho Inoue D, Matsumoto T, Ogata E, Ikeda K. 59) 22-Oxa- TM. Body weight and 25-hidroxyvitamin D follicular calcitriol, a noncalcemic analogue of calcitriol, levels: a prospectivestudy of women submitted to in suppresses both and parathyroid vitro fertilization. JBRA Assist Reprod 2016; 20: 127- hormone-related peptide gene expression in hu- 131. man lymphotrophic virus, type I-infected T Ozkan S, Jindal S, Greenseid K, Shu J, Zeitlian G, cells. J Biol Chem 1993; 268: 16730-16736. 72) Hickmon C, Pal L. Replete vitamin D stores predict Kim M, Fujiki R, Murayama A, Kitagawa H, Yamaoka 60) reproductive success following in vitro fertiliza- K, Yamamoto Y, Mihara M, Takeyama K, Kato S. 1Al- tion. Fertil Steril 2010; 94: 1314-1319. pha,25(OH)2D3-induced transrepression by vita- Estes SJ, Ye B, Qiu W, Cramer D, Hornstein MD, Miss- min D receptor through E-box-type elements in 73) mer SA. the human parathyroid hormone gene promoter. A proteomic analysis of IVF follicular fluid Mol Endocrinol 2007; 21: 334-342. in women

4249 A.S. Laganà, S.G. Vitale, H. Ban Frangež, E. Vrtačnik-Bokal, R. D’Anna

78) Rudick BJ, Ingles SA, Chung K, Stanczyk FZ, Paulson 90) Hammoud AO, Meikle AW, Peterson CM, Stanford RJ, Bendikson KA. Influence of vitamin D levels on J, Gibson M, Carrell DT. Association of 25-hy- in vitro fertilization outcomes in donor-recipient droxy-vitamin D levels with semen and hormonal cycles. Fertil Steril 2014; 101: 447-452. parameters. Asian J Androl 2012; 14: 855-859. 79) Fox C, Morin S, Jeong JW, Scott RT Jr, Lessey 91) Ramlau-Hansen CH, Moeller UK, Bonde JP, Olsen BA. Local and systemic factors and implantation: J, Thulstrup AM. Are serum levels of vitamin D what is the evidence? Fertil Steril 2016; 105: 873- associated with semen quality? Results from 884. a cross-sectional study in young healthy men. 80) Al-Hendy A, Diamond MP, El-Sohemy A, Halder SK. Fertil Steril 2011; 95: 1000-1004. 1,25-dihydroxyvitamin D3 regulates expression of 92) Lerchbaum E, Pilz S, Trummer C, Rabe T, Schenk M, sex steroid receptors in human Heijboer AC, Obermayer-Pietsch B. Serum vitamin cells. J Clin Endocrinol Metab 2015; 100: E572- D levels and hypogonadism in men. Andrology 582. 2014; 2: 748-754. 81) Kavandi L, Collier MA, Nguyen H, Syed V. Pro- 93) Amling M, Priemel M, Holzmann T, Chapin K, gesterone and calcitriol attenuate inflammatory Rueger JM, Baron R, Demay MB. Rescue of the CXCL1 and CXCL2 in ovarian and en- skeletal phenotype of vitamin D receptor-ab- dometrial cancer cells. J Cell Biochem 2012; 113: lated mice in the setting of normal ion 3143-3152. homeostasis: Formal histomorphometric and 82) Lee LR, Teng PN, Nguyen H, Hood BL, Kavandi biomechanical analyses. Endocrinology 1999; L, Wang G, Turbov JM, Thaete LG, Hamilton CA, 140: 4982-4987. Maxwell GL, Rodriguez GC, Conrads TP, Syed 94) Lieben L, Stockmans I, Moermans K, Carmeliet G. V. Progesterone enhances calcitriol antitumor Maternal hypervitaminosis D reduces fetal bone activity by upregulating vitamin D receptor ex- mass and mineral acquisition and leads to neo- pression and promoting apoptosis in endome- natal lethality. Bone 2013; 57: 123-131. trial cancer cells. Cancer Prev Res 2013; 6: 95) Ornoy A. The effects of maternal hypercortison- 731-743. ism and hypervitaminosis D2 on fetal osteogen- 83) Lopes N, Sousa B, Martins D, Gomes M, Vieira D, esis and in rats. Teratology 1971; 4: Veronese LA, Milanezi F, Paredes J, Costa JL, Schmitt 383-394. F. Alterations in Vitamin D ignaling and metabolic 96) Di Spigna G, Del Puente A, Covelli B, Abete E, pathways in cancer progression: a study of Varriale E, Salzano S, Postiglione L. Vitamin D re- VDR, CYP27B1 and CYP24A1 expression in be- ceptor polymorphisms as tool for early screen- nign and malignant breast lesions. BMC Cancer ing of severe bone loss in women patients with 2010; 10: 483. rheumatoid arthritis. Eur Rev Med Pharmacol 84) Swami S, Krishnan A V, Feldman D. Receptor abun- Sci 2016; 20: 4664-4669. dance and suppresses estrogen actions in MCF- 97) Baidal DA, Ricordi C, Garcia-Contreras M, Sonnino 7 human breast cancer cells abundance and sup- A, Fabbri A. Combination high-dose omega-3 presses estrogen actions in MCF-7. Clin Cancer fatty acids and high-dose cholecalciferol in new Res 2000; 6: 3371-3379. onset type 1 : a potential role in preser- 85) King AN, Beer DG, Christensen PJ, Simpson RU, vation of beta-cell mass. Eur Rev Med Pharma- Ramnath N. The vitamin D/CYP24A1 story in col Sci 2016; 20: 3313-3318. cancer. Anticancer Agents Med Chem 2010; 10: 98) Gu SG, Wang CJ, Zhao G, Li GY. Role of vitamin 213-224. D in regulating the neural stem cells of mouse 86) Zeljic K, Supic G, Stamenkovic Radak M, Jovic N, Ko- model with multiple sclerosis. Eur Rev Med zomara R, Magic Z. Vitamin D receptor, CYP27B1 Pharmacol Sci 2015; 19: 4004-4011. and CYP24A1 genes polymorphisms association 99) Turhan Caglar FN, Ungan I, Ksanski V, Opan S, with oral cancer risk and survival. J Oral Pathol Çiftçi S, Kural A, Koyuncu A, Akturk F, Karakaya O. Med 2012; 41: 779-787. Evaluation of serum vitamin D levels in patients 87) Oh JJ, Byun SS, Lee SE, Hong SK, Jeong CW, Choi with X syndrome. Eur Rev Med Pharmacol Sci WS, Kim D, Kim HJ, Myung SC. Genetic variants in 2016; 20: 1155-1160. the CYP24A1 gene are associated with prostate 100) Turkeli A, Ayaz O, Uncu A, Ozhan B, Bas VN, Tufan cancer risk and aggressiveness in a Korean AK, Yilmaz O, Yuksel H. Effects of vitamin D lev- study population. Prostate Cancer Prostatic Dis els on control and severity in pre-school 2014; 17: 149-156. children. Eur Rev Med Pharmacol Sci 2016; 20: 88) Campbell MJ, Reddy GS, Koeffler HP. Vitamin D3 an- 26-36. alogs and their 24-oxo metabolites equally inhibit 101) Dong CH, Gao QM, Wang ZM, Wang AM, Zhen clonal proliferation of a variety of cancer cells but P. Vitamin D supplementation for have differing molecular effects. J Cell Biochem in older adults: can we make it help better? Eur 1997; 66: 413-425. Rev Med Pharmacol Sci 2016; 20: 4612-4621. 89) Yu HM, Li XJ, Kadam AL, Cheng CY, Koide SS. Hu- 102) Shymanskyy IO, Lisakovska OO, Mazanova AO, man testis vitamin D binding protein involved in Riasniy VM, Veliky MM. Effects of vitamin D3 and infertility. Arch Androl; 33: 119-128. on prednisolone-induced alterations

4250 Vitamin D and reproduction

of phagocyte function. Eur Rev Med Pharmacol 105) Bizzarri M. Warning about supplemental of Sci 2016; 20: 1379-1383. Vitamin D in women looking for pregnancy. 103) Mattozzi C, Paolino G, Salvi M, Macaluso L, Luci Eur Rev Med Pharmacol Sci 2016; 20: 2187- C, Morrone S, Calvieri S, Richetta AG. Peripheral 2188. blood regulatory T cell measurements correlate 106) Ross AC, Manson JE, Abrams SA, Aloia JF, Bran- with serum vitamin D level in patients with pso- non PM, Clinton SK, Durazo-Arvizu RA, Galla- riasis. Eur Rev Med Pharmacol Sci 2016; 20: gher JC, Gallo RL, Jones G, Kovacs CS, Mayne 1675-1679. ST, Rosen CJ, Shapses SA. The 2011 report on 104) Dabrowski F, Grzechocinska B, Wielgos M. The role dietary reference intakes for calcium and vi- of vitamin D in reproductive health–A Trojan tamin D from the Institute of Medicine: what horse or the golden fleece? 2015; 7: clinicians need to know. J Clin Endocrinol 4139-4153. Metab 2011; 96: 53-58.

4251