Vitamin D and human reproduction

Transcription

1 Vitamin D and human reproduction Dimitrios G. Goulis Associate Professor of Reproductive Endocrinology Aristotle University of Thessaloniki Secretary General, European Academy of Andrology Secretary General, European Andropause and Menopause Society Unit of Reproductive Endocrinology 1 st Department of Obstetrics and Gynecology Aristotle University of Thessaloniki

2 Conflict of interests During the last two years, I have received educational, travel and research grants from pharmaceutical companies None of these grants can be considered as conflict of interest for this lecture

3 Vitamin D vitamin D 2 vitamin D 3

4 Osteoporosis Inflammation Atherosclerosis Autoimmunity Tumorigenesis Reproduction genomic action non-genomic action

5 4 key questions Are vitamin D system components present in the reproductive system? What do we know about the physiologic role of vitamin D in reproduction? (basic data) What is the clinical evidence for an interplay between vitamin D deficiency and infertility? (clinical data) Vitamin D supplementation during pregnancy

6 4 key questions Are vitamin D system components present in the reproductive system? What do we know about the physiologic role of vitamin D in reproduction? (basic data) What is the clinical evidence for an interplay between vitamin D deficiency and infertility? (clinical data) Vitamin D supplementation during pregnancy

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8 Male reproductive system VDR 1αΟΗ VDR 1αΟΗ VDR 25ΟΗ VDR

9 Male reproductive system VDR 25ΟΗ VDR VDR 1αΟΗ

10 Female reproductive system VDR VDR 1αΟΗ

11 Female reproductive system VDR VDR

12 Female reproductive system VDR VDR 1αΟΗ

13 Conclusions Vitamin D system components are present in all reproductive tissues, in both male and female Vitamin D / VDR are involved in a spectrum of intracellular mechanisms Vitamin D deficiency / VDR polymorphisms have been associated with endometriosis, PCOS and IVF outcome and male infertility (observational and interventional studies) Pregnant women must be supplemented with vitamin D in order to prevent adverse pregnancy outcome, as well as disease in the later life that may have fetal origin

14 4 key questions Are vitamin D system components present in the reproductive system? What do we know about the physiologic role of vitamin D in reproduction? (basic data) What is the clinical evidence for an interplay between vitamin D deficiency and infertility? (clinical data) Vitamin D supplementation during pregnancy

15 4 key questions Are vitamin D system components present in the reproductive system? What do we know about the physiologic role of vitamin D in reproduction? (basic data) What is the clinical evidence for an interplay between vitamin D deficiency and infertility? (clinical data) Vitamin D supplementation during pregnancy

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17 Vitamin D and male reproduction

18 Vitamin D and female reproduction

19 Conclusions Vitamin D system components are present in all reproductive tissues, in both male and female Vitamin D / VDR are involved in a spectrum of intracellular mechanisms Vitamin D deficiency / VDR polymorphisms have been associated with endometriosis, PCOS and IVF outcome and male infertility (observational and interventional studies) Pregnant women must be supplemented with vitamin D in order to prevent adverse pregnancy outcome, as well as disease in the later life that may have fetal origin

20 4 key questions Are vitamin D system components present in the reproductive system? What do we know about the physiologic role of vitamin D in reproduction? (basic data) What is the clinical evidence for an interplay between vitamin D deficiency and infertility? (clinical data) Vitamin D supplementation during pregnancy

21 4 key questions Are vitamin D system components present in the reproductive system? What do we know about the physiologic role of vitamin D in reproduction? (basic data) What is the clinical evidence for an interplay between vitamin D deficiency and infertility? (clinical data) Vitamin D supplementation during pregnancy

22 Vitamin D and reproduction In normal men Deterioration in semen quality during spring Positive association between 25(OH)D concentrations and testosterone In normal women Seasonal variability in delivery rates and quality of embryo rates after IVF, with the highest values to occur during spring and the lowest during autumn Possible explanations Vitamin D, melatonin, serotonin, endogenous opioids

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24 Endometriosis Inflammation Autoimmunity

25 Vitamin D and Gynecology

26 Polycystic ovary syndrome Insulin secretion Obesity

27 Vitamin D and Gynecology

28 Assisted Reproduction Techniques Vitamin D in follicular fluid

29 Vitamin D and Gynecology

30 Submitted for publication

31 Screening Included Eligibility Identification Records identified through MEDLINE database (n = 180) Records after duplicates removed (n = 214) Records screened (n = 214) Full-text articles assessed for eligibility (n = 18) Studies included in qualitative synthesis (n = 17) Additional records identified through Cochrane database (n = 34) Records excluded (n = 196) Full-text articles excluded, with reasons (n = 1) Vitamin D metabolites and endometriosis (n = 8) Vitamin D binding protein and endometriosis (n = 6) Vitamin D receptor and endometriosis (n = 3) Vitamin D key enzymes and endometriosis (n = 2)

32 id Study Main findings Vitamin D metabolites and endometriosis 1. Hartwell et al., 1990 Higher serum 1,25(OH)2D3 (p < 0.001), but not 25(OH)D3 in endometriosis group 2. Agic et al., 2007 Similar serum 25(OH)D3 (p = 0.31) in both groups 3. Somigliana et al., 2007 Higher serum 25(OH)D 3 (p = 0.05) in endometriosis group 4. Harris et al., 2012 Plasma 25(OH)D3 concentration negatively correlated with endometriosis 5. Pagliardini et al., 2015 Higher serum 25(OH)D3 (p = 0.01) in endometriosis group 6. Miyashita et al., 2016 Lower serum 25(OH)D 3 in severe (p = 0.05) and mild (p = 0.01) endometriosis groups 7. Dressler et al., 2016 Similar serum 25(OH)D3 (p = 0.40) in both groups 8. Ciavattini et al., % of patients with a single ovarian endometrioma had hypovitaminosis D Positive correlation between serum 25(OH)D3 and the diameter of ovarian endometriomas (r = 0.3, p = 0.03) Vitamin D binding protein (VDBP) and endometriosis

33 Positive correlation between serum 25(OH)D3 and the diameter of ovarian endometriomas (r = 0.3, p = 0.03) Vitamin D binding protein (VDBP) and endometriosis 1. Ferrero et al., 2005 Lower expression of a VDBP isoform (VDBPE) in the peritoneal fluid (p < 0.05) in endometriosis group No difference in VDBPE expression in plasma Endometriosis and oral contraceptives groups had higher VDBP concentrations both in plasma (p < 0.05) and in peritoneal fluid (p < 0.05) compared to untreated endometriosis group 2. Borkowski et al., 2008 No difference in VDBP concentration in both serum (p = 0.49) and peritoneal fluid (p = 0.63) No difference when endometriosis group subdivided according to the severity of disease 3. Ferrero et al., 2009 VBDP concentration in peritoneal fluid of endometriosis group significantly down-regulated (p < 0.001) during treatment with GnRH-a compared with untreated endometriosis group 4. Faserl et al., 2011 Higher expression of serum VDBP (p < 0.02) and VDBP GC2 allele product (p = 0.006) in endometriosis group 5. Cho et al., 2012 Higher urinary VDBP concentrations (p = 0.001) in endometriosis group Limited value as diagnostic marker for endometriosis alone (sensitivity 58%, specificity 76%) or in combination with CA Hwang et al., 2013 Higher expression of VDBP in ectopic endometrial tissue compared with normal endometrial tissue (p < 0.01)

34 control group Vitamin D receptor (VDR) and endometriosis 1. Agic et al., 2007 Higher VDR mrna in endometrium of endometriosis group in isolated epithelial cells compared to stromal cells (p < 0.01); this trend was not statistically significant in control group Higher VDR mrna expression in both epithelial (p < 0.01) and stroma cells (p < 0.01) of endometriosis group The observed differences in VDR mrna concentrations were maintained at the protein level (Western blot analysis) 2. Vilarino et al., 2011 No differences in VDR gene polymorphisms between the two groups 3. Szczepanska et al., 2015 Correlation between A-T BmsI/FokI and endometriosisassociated infertility (p = 0.011) No other associations between VDR haplotypes and endometriosis Vitamin D key enzymes and endometriosis 1. Viganò et al., 2006 Higher 1α-hydroxylase (p = 0.03) in endometrium of

35 endometriosis Vitamin D key enzymes and endometriosis 1. Viganò et al., 2006 Higher 1α-hydroxylase (p = 0.03) in endometrium of endometriosis group in both mrna and protein levels Higher 25α-hydroxylase mrna in ovarian tissue of endometriosis group in comparison with ovarian cancer group (p < 0.01) 2. Agic et al., 2007 Higher 1α-hydroxylase (p < 0.05) in proliferative phase endometrium of endometriosis group in both mrna and protein levels

36 Conclusions Vitamin D system components are present in all reproductive tissues, in both male and female Vitamin D / VDR are involved in a spectrum of intracellular mechanisms Vitamin D deficiency / VDR polymorphisms have been associated with endometriosis, PCOS and IVF outcome and male infertility (observational and interventional studies) Pregnant women must be supplemented with vitamin D in order to prevent adverse pregnancy outcome, as well as disease in the later life that may have fetal origin

37 4 key questions Are vitamin D system components present in the reproductive system? What do we know about the physiologic role of vitamin D in reproduction? (basic data) What is the clinical evidence for an interplay between vitamin D deficiency and infertility? (clinical data) Vitamin D supplementation during pregnancy

38 4 key questions Are vitamin D system components present in the reproductive system? What do we know about the physiologic role of vitamin D in reproduction? (basic data) What is the clinical evidence for an interplay between vitamin D deficiency and infertility? (clinical data) Vitamin D supplementation during pregnancy

39 Vitamin D status deficiency insufficiency sufficiency

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41 Vitamin D deficiency in pregnancy

42 Vitamin D epimers

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44 Fetal origin of adult disease Inadequate maternal vitamin D concentrations during pregnancy are associated with reduced whole body and lumbar spine bone mineral content in their 9-year old offspring As vitamin D is fundamental for brain development during pregnancy, low concentrations of maternal vitamin D during the third trimester of pregnancy have been associated with increased risk of schizophrenia

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46 Vitamin D and Pregnancy

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48 25(OH)D Pre-eclampsia Gestational diabetes

49 SGA Low birth weight Preterm birth

50 Birth weight Birth length Cesarean section

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52 Vitamin D sources

53 Recommended Dietary Allowance ΗλικίαAge Men Women Pregnancy Lactation 0-12 months ΙU ΙU (10-25 µg) (10-25 µg) 1-13 years IU IU (15-75 µg) (15-75 µg) years IU IU IU IU ( µg) ( µg) ( µg) ( µg) years IU IU IU IU ( µg) ( µg) ( µg) ( µg) years IU IU ( µg) ( µg) > 70 ετών IU IU ( µg) ( µg) 40 international units (IU) = 1 µg

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55 Possible explanations Study design (lack of a specific outcome, timing of supplementation, participants with heterogeneous vitamin D status) Pitfalls in the interpretation of vitamin D equilibrium (plasma half-life) Supplementation regimen (wide range of regimens: dose, bolus and form) Geographical characteristics (wide range of latitude gradient) Adaptations of vitamin D metabolism during pregnancy (vitamin D and calcium equilibrium) Supplementation of populations with low baseline 25(OH)D (likely to manifest beneficial effects)

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61 Conclusions Vitamin D system components are present in all reproductive tissues, in both male and female Vitamin D / VDR are involved in a spectrum of intracellular mechanisms Vitamin D deficiency / VDR polymorphisms have been associated with endometriosis, PCOS and IVF outcome and male infertility (observational and interventional studies) Pregnant women must be supplemented with vitamin D in order to prevent adverse pregnancy outcome, as well as disease in the later life that may have fetal origin

62 Vitamin D The old model The new model

63 4 key questions Are vitamin D system components present in the reproductive system? What do we know about the physiologic role of vitamin D in reproduction? (basic data) What is the clinical evidence for an interplay between vitamin D deficiency and infertility? (clinical data) Vitamin D supplementation during pregnancy

64 Conclusions Vitamin D system components are present in all reproductive tissues, in both male and female Vitamin D / VDR are involved in a spectrum of intracellular mechanisms Vitamin D deficiency / VDR polymorphisms have been associated with endometriosis, PCOS and IVF outcome and male infertility (observational and interventional studies) Pregnant women must be supplemented with vitamin D in order to prevent adverse pregnancy outcome, as well as disease in the later life that may have fetal origin

65 Unit of Reproductive Endocrinology Associate professor D.G. Goulis Professor emeritus J. Papadimas PhD candidates and Post-doc researchers C. Tsametis (endocrinologist) P. Poulakos (endocrinologist) P. Iliadou (endocrinologist) C. Dimopoulou (endocrinologist) E. Kintiraki (endocrinologist) S. Paschou (endocrinologist) P. Anagnostis (endocrinologist) I. Litsas (endocrinologist) G. Kanakis (endocrinologist) G. Mintziori (endocrinologist) A. Mousiolis (endocrinologist) E. Billa (endocrinologist) K. Papadimitriou (endocrinologist) V. Harizopoulou (midwife) E. Tsirou (endocrinologist - dietician) E. Taousani (midwife) D. Savvaki (physical education) N. Athanasiadi (dietician) I. Koptsi (psychologist) Departments of Physical Education Professor emeritus S. Tokmakidis Associate professor K. Dipla Associate professor A. Zafiridis 1 st Department of Obstetrics and Gynecology Aristotle University of Thessaloniki Professor G.F. Grimbizis