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Genevieve Neal-Perry, MD PhD Associate Professor Ob/Gyn and Neuroscience Fellowship Director, Division of Reproductive Endocrinology and Infertility Albert.

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Presentation on theme: "Genevieve Neal-Perry, MD PhD Associate Professor Ob/Gyn and Neuroscience Fellowship Director, Division of Reproductive Endocrinology and Infertility Albert."— Presentation transcript:

1 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 1) To describe vitamin D 3 physiology 2) To discuss the differential impact of in utero + perinatal vs. pubertal vitamin D 3 deficiency on a.puberty b.reproductive physiology i.Hypothalamus ii.Pituitary iii.Ovary

3 1) Fat soluble steroid hormone  vitamin D 3 steroid hormone receptor (VDR)  RXR 2) Genomic vs. non- genomic classical non-classical

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

5 GroupFDA Recommend Dose (IU) Safe High FDA (IU) Toxic Dose Best Dose Infants 0-12 months 400*< Children600*2000≥ Pregnant Women 600* ,000 per day** ≥ D3 /day 50,000 D2/2 week 50,000 D2/month Lactating Women 600* Adults <50600* Adults * Adults >70800* *RDA and IOM recommendations**safe for at least 5 months

6 Sunshine Cod liver oil (tbsp) Cooked salmon (3 ½ oz) Milk (8 oz) Cereal (8 oz) Egg Yolk Swiss cheese ( 1 oz) Warning Label ! To achieve the daily recommendation of 600 IU of vitamin D 3 you have to eat: 30 eggs = 50 cubes of Swiss cheese =120 oz of cereal = 6 cups milk Dietary Sources of Vitamin D 3 FoodServingVitamin D (IU) Cod Liver Oil1 Tbsp1360 Cooked Salmon3 ½ oz360 Cooked Mackerel3 ½ oz345 Canned Tuna Fish3 oz200 Canned Sardines1 ¾ oz250 Fortified OJ8 oz100 Fortified Milk8 oz98 Fortified cereal8 oz40 Egg (yolk)1 egg20

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8 Health Implications StatusSerum 25(OH)D 3 nmol/literng/ml Deficient<30<12 Insufficient Adequate Toxic>125>50

9 1) People with dark skin pigmentation  African American > Hispanic > Caucasian 2) Obese individuals 3) Elderly 4) Reproductive-aged women, neonates, and adolescents

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11 Yetley, Am J Clin Nutr 2008:88(2): 558S National Health and Nutrition Examination Survey % <50 nmol/L vit D 3

12 Yetley, E. A Am J Clin Nutr 2008;88:558S

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15 “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!!

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17 Vitamin D3 deficiency PCOS and Obesity Recurrent pregnancy loss Infertility Small for gestational age

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19 Overarching Objective To determine the mechanism (s) by which VD 3 regulates female reproduction

20 Overarching Hypothesis Developmental VD 3 deficiency disrupts hypothalamic-pituitary- gonadal physiology in females

21 1) VDR and α-hydroxylase (cyp27b1) is widely distributed in reproductive tissue 2) Vitamin D 3 is necessary for neuronal development 3) Vitamin D 3 deficiency in humans is associated with reproductive dysfunction 4) Rodent models of vitamin D 3 deficiency a.diet induced vitamin D 3 deficiency in rats b.Transgenic mice

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23 1) Transgenic cyp27b1 null mice 2) Wild type littermates

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25 preconceptionperinatal birthweaning on day 21 peripubertalintrauterine conception 1) Vaginal opening 2) 1 st estrus 3) Estrous cycling Group 1: Control WT and KO (VD 3 sufficient diet throughout) Group 3: KO in utero and perinatal VD 3 deficient diet Group 4: KO peripubertal VD 3 deficient diet Group 2 Group 3Group 4 Group 2: KO in utero, perinatal and peripubertal VD 3 deficient diet

26 Mice exposed to in utero, perinatal and peripubertal VD 3 deficiency have a delayed puberty VO1 st estrus Days between VO and 1 st estrus preconception perinatal birth Weaning D21 peripubertalin utero conception VO 1st Estrus Group 2

27 preconception perinatal birth weaning D21 peripubertalin utero conception VO 1st Estrus Group 3 Will in utero and perinatal VD 3 deficiency disrupt puberty? VO 1 st estrus Days between VO and 1 st estrus

28 Will peripubertal VD 3 deficiency disrupt puberty? preconception perinatal birth Weaning D21 peripubertal In utero conception VO 1 st estrus Group 4 VO1 st estrus Days between VO and 1 st estrus

29 Modified from Roa et al., Molecular and Cellular Endocrinology 324(2010):87 Genetic background

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35 * p<0.05 P (ng/ml) Prl (ng/ml) E 2 (pg/ml) LH (ng/ml) FSH (ng/ml) Estrus Diestrus-1 Diestrus-2 Proestrus Estrus

36 LH surge

37 a, P<0.01 vs. WT; b, P<0.05 vs. D+

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

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40 KO (D-) + saline KO (D-) + PMSG + hCG CL VD 3 deficiency does not affect ovarian responsiveness to superovulation

41 N= 3-8 Follicle Stimulating Hormone

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43 Negative Control GT1-7Kidney GT1-7 Kidney VDR

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45 VD 3 + VD 3 - Peripubertal VD 3 deficiency does not affect GnRH neuron density

46 1) Delays the puberty 2) Reversibly disrupts estrous cyclicity 3) Does not primarily affect ovarian physiology 4) Does not affect GnRH neuron density 5) Does not disrupt negative feedback effects of estradiol during diestrus 6) GT1-7 neurons express VDR

47 1) Changes in dietary habits and reduced sun exposure have resulted in near epidemic levels of VD 3 insufficiency & deficiency 2) Vitamin D 3 insufficiency & deficiency disproportionately affect reproductive aged women, neonates and adolescents thereby making these groups more susceptible to the adverse consequences of VD 3 deficiency on the reproductive axis

48 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 R21HD Zondek Award for Reproductive Research Department of Ob/Gyn Einstein College of Medicine Cary Dicken REI fellow Jun Shu, technician Joe Davis REI fellow Yan Sun Post Doc


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