Investigation of the infertile obese woman: the laboratory s role R. LEVY and I. CEDRIN-DURNERIN, DURNERIN P. LEVEILLE, N. SERMONDADE, C. FAURE, S. HERCBERG and S. CZERNICHOW Histologie Embryologie Cytogénétique CECOS, CHU Jean Verdier, Bondy UMR Inserm U557 / Inra /Cnam /Paris 13, épidémiologie nutritionnelle - Pr. S. Hercberg OBESITY OBESITY ObEpi - Roche National Study 2009 : - Overweight : 26% women - Obesity : 15% women Increase of weight women of childbearing age 0.5 to 0.7 kg /year
ABOUT QUANTITY AND QUALITY < 2/3 of Dietary Reference Intake Deficiency POOR NUTRITION VITAMINS Vitamin B1 - B6 : 30-50% W Vitamin C : 20% Vitamin A : 30-45% Vitamin E : 40-60% MINERALS Fe >90% Cu and Zn : 25-50% Ca : 8% of M, 15% of W Mg : 18% of M et 23% W VITAMINS Vitamin B1: 22% Vitamin B2 : 30% W, 22% M Vitamin B6 : 25% W, 15% M Vitamin C : 5% W, 12% M Vitamin A : 20-25% W Vitamin D : 12% of M, 15%W MINERALS Fe : 25% W Cu : 5% W, 15% of M Se : 30% Maternal nutritional imprinting development Developmental origins of Health and Disease DOHaD Adult Nuclear organization oga a o MZT Blastocyst gonad differenciation Adolescent Birth d e v e l o p m e n t a l o r i g i n s of health and disease (DOHaD oocyte embryo implantation time in vitro medium, ART Maternal nutrition D après Pascale Chavatte-Palmer, INRA
INVESTIGATION OF THE OBESE INFERTILE WOMEN History Familial and personal history Diabetes mellitus, HTA, thyroid LED, SAPL Phlebitis, heart, kidney Physical examination Weight, BMI, abdominal obesity+++ Pilosity Cycles, menstruation Ultrasound and radio Hormonal evaluation FSH, LH, E2, P4 PRL TSH. Androgens ++++ Testosterone (T) in first intention, According to the results: -4 androstenedione ( 4) dehydroepiandrosterone (DHEAS) 21-hydroxylase (17OHP) Sex Hormone Binding Globulin (SHBG) Metabolic syndrome HDL, LDL, total cholesterol, TG (dyslipidaemia) Fasting Blood Glucose, postprandial glucose test, Hb1ac (glucose intolerance) Insulin (insulin resistance, IR) and C peptide Ferritin, Transferrin Creatinine NUTRITION C-Reactive Protein CRP ADIPOKINES : resistin, PAI-1, adiponectin, leptin CYTOKINES : IL1, IL6, TNF α INFLAMMATION METABOLIC SYNDROME A waist circumference 88 cm for women A blood pressure of 130/85 mm Hg A triglyceride level 150 mg/dl (1.7 mmol/l) A fasting blood glucose (sugar) level 100 mg/dl (6.1 mmol/l) A high density lipoprotein level (HDL) 50 mg/dl or 1.3 mmol/l
Impact of obesity on woman fertility? Jungheim and Moley, 2010
BMI, MATERNAL BIRTHWEIGHT AND TIME TO PREGNANCY Low/High h birth weight Prematurity impact on TTP Nohr et al., 2009 BMI AND OVULATION Nurses health study 2527 female nulliparous nurses risk 24<BMI<26 Risk X 3,7 for BMI>30
BMI AND TIME-TO-PREGNANCY Probability to conceive decreases if BMI > 29 3029 subfertile couples women with high BMI had a 4% lower pregnancy rate/kg/m² increase 1651 Danish women between 2007-2008 (Snart Gravid Study) Longer TTP among overweight, obese and very obese women (stronger association among young women aged < 25 years) Longer TTP when weight gain (>15kg) since age 17 Two out of 3 criteria : Oligo- and/or anovulation Clinical and/or biochemical signs of hyperandrogenism Polycystic ovaries
Impact on oocyte? CONTROVERSY!! Impact on embryo? Impact on implantation? Robker 2008; Pandey 2010, Sathya 2010, Bellver 2010 OOCYTE QUALITY MP + ROS - Glutathione Oxidative stress (Probe : TMRM Tétramethyl rhodamine methylester) supplemented with micronutrient mineral mix AIN93G High dietary MP Control + Lipids High fat diet (Probe : JC-1tetraethylbenzimidazolylcarbocyanine iodide ) High fat diet SF00-219
BMI AND ENDOMETRIUM O.D. 6500 IVF/ICSI Bellver, 2008 Role of uterine environment Bellver, 2010 Oxidative stress
BMI AND MISCARRIAGE High risk BMI>25kg/m² High risk after ovulation induction Significative in oocyte donation No significative in IVF/ICSI OR,1.67; 95% CI,1.25-2.25 Higher risk in obese and underweight women! Lower chance of pregnancy More gonadotrophin needed d Lower number of retrieved oocytes Increased miscarriage rate Should access to fertility treatment be determined by female BMI? Maheshwari, 2007
BODY FAT DISTRIBUTION Increase of abdominal fat 36 % of women with waist circumference > 88 cm (ObEpi 2009) A 0,1 unit increase in waist-hip ratio leads to a 30% decrease in probability of conception/cycle Zaadstra et al., 1993 NORMAL WEIGHT OBESE SYNDROME Continuum between normal weight and overweight The proinflammatory cytokines : significant prognostic indicators of the risk of obesity, CVD, and the metabolic syndrome in NWO women ADIPOSOPATHY
RESEARCH Number of the genes whose transcript abundance is altered in the PCOS oocyte contain putative nuclear receptor binding sites suggesting that pharmacological or lifestyle interventions might correct the molecular defects in the PCOS oocyte and improve pregnancy outcome. The finding of unique gene expression patterns in cumulus cells from the two PCOS subtypes is in agreement with other studies that have found the two to be separate entities with potentially different pathophysiologies. FOLLICULAR ENVIRONMENT Follicular fluid insulin, triglycerides, and C-reactive protein SHBG LOCAL FOLLICULAR FLUID INFLAMMATION High TNFα and low IL-6 mrna expression of obese patients
Impact of male obesity on fertility? SPERM QUALITY? Decrease of 1% / years of mean number of spermatozoa OBESITY! Overweight (30-50%) Obesity (>15%) Monitoring national du risque artériel, MONA LISA 2005-2007; OBEPI 2009
BMI AND SPERM Decrease of NMS (quantity) Negative correlation between waist-to-hip ratio and concentration of spermatozoa Increase of DNA fragmentation of spermatozoa (quality) Sperm binding Impact of obesity on offspring health?
IGF-I receptor expression in blastocytes (p<0.001) IGF2R mrna (p<0.001) More apoptosis In fetuses and pups Smaller fetuses (p<0.001) 001) Larger pups at 13 wk Glucose intolerance and increased cholesterol Oxidative stress
Paternal nutritional imprinting THE LABORATORY S ROLE METABOLIC Total cholesterol, LDL, HDL, triglycerides Glycemic status, Insulin, C peptide, leptin, SHBG HORMONAL LH, FSH, E2, total and free testosterone, inhibin EXTRA ANALYSIS Makers of oxidative stress : polymorphism, antioxydant enzyme activities, i i pro/antioxydant component Adipokine and inflammation makers : PAI1, TNFα, IL1, IL6 RESEARCH Omics Genomic, transcriptomic, metabolomic
NUTRITION AND FERTILITY : Research Projects «NUTRIOVUL» : Impact of diet and nutritional status on the ovulation disturb «ALIFERT»: Relation between diet and fertility www.alifert.fr «METASPERME»: Impact of metabolic syndrome on sperm parameters and oxidative stress www.alifert.fr