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Vitamin D 3 and Female Reproduction: A Role Beyond Bone Health

Vitamin D 3 and Female Reproduction: A Role Beyond Bone Health. Genevieve Neal-Perry, MD PhD Associate Professor Ob/ Gyn and Neuroscience Fellowship Director, Division of Reproductive Endocrinology and Infertility Albert Einstein College of Medicine and Montefiore Medical Center.

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Vitamin D 3 and Female Reproduction: A Role Beyond Bone Health

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  1. Vitamin D3 and Female Reproduction: A Role Beyond Bone Health Genevieve Neal-Perry, MD PhD Associate Professor Ob/Gyn and Neuroscience Fellowship Director, Division of Reproductive Endocrinology and Infertility Albert Einstein College of Medicine and Montefiore Medical Center

  2. Objective • To describe vitamin D3 physiology • To discuss the differential impact of in utero+ perinatal vs. pubertal vitamin D3 deficiency on • puberty • reproductive physiology • Hypothalamus • Pituitary • Ovary

  3. Vitamin D3 • Fat soluble steroid hormone • vitamin D3 steroid hormone receptor (VDR) • RXR • Genomic vs. non-genomic non-classical classical

  4. UV-B 20-30 min 2x wk Calicidiol ½ life =15 d Caltriol ½ life =15 h

  5. Vitamin D3 Requirements *RDA and IOM recommendations **safe for at least 5 months

  6. Warning Label ! To achieve the daily recommendation of 600 IU of vitamin D3 you have to eat: 30 eggs = 50 cubes of Swiss cheese =120 oz of cereal = 6 cups milk Swiss cheese ( 1 oz) Cod liver oil (tbsp) Sunshine Milk (8 oz) Cereal (8 oz) Egg Yolk Cooked salmon (3 ½ oz)

  7. Who is at Risk for Vitamin D3 Deficiency? • People with dark skin pigmentation • African American > Hispanic > Caucasian • Obese individuals • Elderly • Reproductive-aged women, neonates, and adolescents

  8. Vitamin D3 deficiencyRacial, Sex and Age disparities

  9. Reproductive-aged women and neonates represent one of the largest groups with vitamin D3 deficiency % <50 nmol/L vit D3 Yetley,Am J ClinNutr2008:88(2): 558S National Health and Nutrition Examination Survey 2000-2004

  10. Racial disparities in mean serum 25-OH D3 concentration from the National Health and Nutrition Examination Survey 2000-2004 Yetley, E. A Am J ClinNutr2008;88:558S

  11. Increasing weight and black race widens disparities in vitamin D3 deficiency

  12. Why should Ob/Gyn MDs be concerned about sex and racial disparities in vitamin D3 deficiency?

  13. “2 out of every 3 pregnant women in the U.S. have suboptimal vitamin D status, with even higher prevalences reported among African-American and Hispanic women” [Looker, et al. Am J Clin Nutrition 2008] Increased medical costs!!

  14. Vitamin D3 Deficiency and Reproductive Health

  15. In the lab……

  16. Overarching Objective To determine the mechanism (s) by which VD3 regulates female reproduction

  17. Overarching Hypothesis Developmental VD3deficiency disrupts hypothalamic-pituitary-gonadal physiology in females

  18. Rationale • VDR and α-hydroxylase (cyp27b1) is widely distributed in reproductive tissue • Vitamin D3 is necessary for neuronal development • Vitamin D3 deficiency in humans is associated with reproductive dysfunction • Rodent models of vitamin D3 deficiency • diet induced vitamin D3 deficiency in rats • Transgenic mice

  19. Objective #1Determine the effect of developmental VD3 deficiency on puberty

  20. Experimental Model • Transgenic cyp27b1 null mice • Wild type littermates

  21. Experimental Design

  22. Group 1: Control WT and KO (VD3 sufficient diet throughout) Group 2: KO in utero, perinatal and peripubertal VD3 deficient diet Group 3: KO in utero and perinatal VD3 deficient diet Group 4: KO peripubertal VD3 deficient diet Group 2 Group 4 Group 3 preconception intrauterine perinatal peripubertal conception birth weaning on day 21 1) Vaginal opening 2) 1st estrus 3) Estrous cycling

  23. Mice exposed to in utero, perinatal and peripubertal VD3 deficiency have a delayed puberty Does in utero, perinatal and peripubertal VD3 deficiency affect puberty? Group 2 Days between VO and 1st estrus VO 1st estrus preconception in utero perinatal peripubertal VO 1st Estrus conception birth Weaning D21

  24. VD3 deficiency restricted to pregnancy and lactation does not disrupt puberty. Will in uteroand perinatal VD3 deficiency disrupt puberty? Group 3 Days between VO and 1st estrus VO 1st estrus preconception in utero peripubertal perinatal conception birth weaning D21 VO 1st Estrus

  25. Peripubertal VD3 deficiency delays puberty. Will peripubertal VD3 deficiency disrupt puberty? Group 4 Days between VO and 1st estrus VO 1st estrus In utero perinatal preconception peripubertal VO 1st estrus conception birth Weaning D21

  26. Modifiers of the pubertal transition Genetic background Modified from Roa et al., Molecular and Cellular Endocrinology 324(2010):87

  27. Is the effect of peripubertal VD3 deficiency on puberty associated with the Cyp27b1 knockout?

  28. VD3 deficiency does not significantly affectperipubertalgrowth curves

  29. Objective #2To determine if VD3 deficiency affects estrous cyclicity

  30. The mouse estrous cycle: the rodent equivalent of the menstrual cycle

  31. Peripubertal VD3 deficiency extends the estrous cycle *

  32. Peripubertal VD3 deficiency disrupts the estrous cycle P (ng/ml) Prl (ng/ml) E2 (pg/ml) LH (ng/ml) FSH (ng/ml) Estrus Diestrus-1 Diestrus-2 Proestrus Estrus * p<0.05

  33. Peripubertal VD3 deficiency disrupts the estrous cycle LH surge LH surge LH surge

  34. Will VD3 supplementation restore the estrous cycle in adults exposed to peripubertalVD3 deficiency? a, P<0.01 vs. WT; b, P<0.05 vs. D+

  35. Communication between the brain and the ovaries change with increasing reproductive age. estradiol ovarian egg development Female reproductive physiology Progesterone

  36. Objective #3To determine if VD3 deficiency disrupts ovarian and/or hypothalamic-pituitary physiology

  37. VD3 deficiency is associated with arrested follicular development VD3 deficiency does not affect ovarian responsiveness to superovulation KO (D-) + saline KO (D-) + PMSG + hCG CL CL CL CL CL

  38. Peripubertal VD3 deficiency does not affect diestrus LH and FSH release? Follicle Stimulating Hormone N= 3-8

  39. Is VDR expressed in GnRH neurons? Negative Control GT1-7 Kidney GT1-7 Kidney VDR

  40. Does peripubertal VD3 deficiency affect GnRH neuron density?

  41. PeripubertalVD3 deficiency does not affect GnRH neuron density VD3+ VD3-

  42. Summary of peripubertal VD3 deficiency • Delays the puberty • Reversibly disrupts estrous cyclicity • Does not primarily affect ovarian physiology • Does not affect GnRH neuron density • Does not disrupt negative feedback effects of estradiol during diestrus • GT1-7 neurons express VDR

  43. Conclusion • Changes in dietary habits and reduced sun exposure have resulted in near epidemic levels of VD3 insufficiency & deficiency • Vitamin D3 insufficiency & deficiency disproportionately affect reproductive aged women, neonates and adolescents thereby making these groups more susceptible to the adverse consequences of VD3 deficiency on the reproductive axis

  44. Acknowledgments • Cary Dicken, MD • Joe Davis, MD • Yan Sun, MD PhD • Jun Shu, MD • Davelene Israel PhD Anne Etgen,PhD Nanette Santoro, MD John Hardin MD Streamson Chua, MD PhD Support • R21HD0663511 • Zondek Award for Reproductive Research Department of Ob/Gyn Einstein College ofMedicine Cary Dicken REI fellow Jun Shu, technician Yan Sun Post Doc Joe Davis REI fellow

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